Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]1[O:31][C:30]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=2[O:21]1>C(Cl)(Cl)Cl>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][NH:8][C:6]([C:5]1[C:4]([O:18][CH3:19])=[CH:3][C:2]([NH:1][C:25]([C:24]2[CH:28]=[CH:29][C:30]3[O:31][CH2:20][O:21][C:22]=3[CH:23]=2)=[O:26])=[CH:17][CH:16]=1)=[O:7])[CH3:15]
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
200 mg (0.75 mmol) of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide in 10 ml of chloroform is mixed with 5 ml of 3,4-methylenedioxybenzoic acid chloride (in chloroform) and this mixture is stirred for 3 hours at room temperature. After concentration by evaporation in a vacuum, the residue is taken up in 40 ml of dilute sodium bicarbonate solution and then extracted with 40 ml of methylene chloride. The methylene chloride phase is washed with water, dried, filtered and concentrated by evaporation. The crude product, 315 mg, is taken up in methylene chloride and purified on silica gel. As a mobile solvent, a mixture that consists of methylene chloride/methanol (977:3→90:10) is used. 210 mg (67% of theory) of benzo[1,3]dioxole-5-carboxylic acid [4-(2-diethylamino-ethylcarbamoyl)-5-methoxy-phenyl]-amide (melting point 131.1° C.) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36](O)=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:15]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][NH:10][C:11](=[O:14])[NH:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1

Procedure:
5-(4-Amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyrimidin-2-one (22 mg, as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol) as described in Example 1, step (1) to obtain the title compound (14 mg, over two steps) after purification on silica (3% MeOH-EtOAc): Mass spectrum (ESI, m/z): Calcd. for C27H36N6O3Si, 521.2 (M+H), found 521.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][C:12]1([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:4][N:3]=1
Reactant: FC1(F)CC1CBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The mixture of 5.00 g (28.7 mmol) of 2-bromo-5-hydroxypyridine, 6.14 g (35.9 mmol) of 1-bromomethyl-2,2-difluorocyclopropane and 9.93 g (71.8 mmol) of K2CO3 in 100 ml ACN is stirred at 70° C. for 14 h. The reaction mixture is diluted with EtOAc, washed with water and 1N aq. NaOH, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=1>O1CCCC1>[C:2]1(=[CH:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C1CCCC1)c1cccnc1
Temperature: 5 °C
Reaction time: 1.33 h
Yield: 61.8 %

Procedure:
A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran (1000 ml) at 2° C. was treated with vigorous stirring under an atmosphere of argon, with potassium t-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5° C. for 80 minutes and then treated with pyridine-3-carbaldehyde (58.9 g, 0.55 mol) during a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then at 20° C. for 18 hours. The tetrahydrofuran was removed in vacuo (30° C.; 14 mmHg) and the residue extracted with pentane (2×500 ml). After treatment with decolourising charcoal (5 g), the mixture was filtered through a plug of flash silica gel (Merck 70-230 mesh; 13cm×2 cm diameter) The filtrate was concentrated in vacuo (30° C., 14 mmHg; then 20° C., 0.01 mmHg) to afford 3-cyclopentylidenemethylpyridine (54 g, 0.34 mol) as an orange oil which was used without further purification;
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:13])[CH2:10][O:11][CH3:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][CH2:8][CH:9]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][O:11][CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(O)COC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(COC)OS(C)(=O)=O
Reaction time: 72 h

Procedure:
4.3 mL of methanesulfonyl chloride was added dropwise at 5° C. to a stirred solution of 6.0 g of 1,3-dimethoxy-propan-2-ol and 9.0 mL of triethylamine in 60 mL of dichloromethane. Stirring was continued for 72 hours at room temperature, followed by extraction with water. The combined organic extracts were dried (sodium sulfate) and concentrated and the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 2.5 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester as an oil. EI-MS: 198 (M+).
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.[ClH:15]>CCO.[Pd]>[ClH:15].[N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccncc2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)CNCC2
Reaction time: 16 h

Procedure:
10% Pd/C (40 mg) was added to a stirred solution of Ethyl imidazo[1,2-a]pyrazine-2-carboxylate (410 mg, 2.15 mmol) and conc.HCl (0.5 mL) in EtOH (9.5 mL) under inert atmosphere. The reaction mixture was stirred continuously under hydrogen atmosphere for 16 h. The reaction mixture was filtered over a celite bed-and the filtrate was concentrated under reduced pressure to afford a solid product, which was washed with diethyl ether and dried to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.C([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[O:36]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:32]([O-:34])=O)[N:30]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].[NH2:57][C@@H:58]1[C:77](=[O:78])[N:60]2[C:61]([C:70]([O:72]C(C)(C)C)=[O:71])=[C:62]([C@H:65]3[CH2:69][CH2:68][CH2:67][O:66]3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[OH:36])/[C:32]([NH:57][C@@H:58]2[C:77](=[O:78])[N:60]3[C:61]([C:70]([OH:72])=[O:71])=[C:62]([CH:65]4[CH2:69][CH2:68][CH2:67][O:66]4)[CH2:63][S:64][C@H:59]23)=[O:34])[N:30]=1
Reactant: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C4CCCO4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 151.3 %

Procedure:
Methanesulphonyl chloride (96 μl, 1.25 mmol) was added to sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (852 mg, 1.2 mmol) in DMF (2 ml) at <-40° C. The mixture was stirred 0.5 h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (326 mg, 1 mmol) in DMF (2 ml), followed by pyridine (101 μl, 1.25 mmol), were added. The reaction was stirred for 1 h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated in vacuo and flash chromatographed eluting with 25, 30% ethyl acetate in hexane to give the title compound as a colourless foam (665 mg, 68%); νmax (CH2Cl2) 3395, 1787, 1722, 1687, 1527, 1449, 1156 and 1051 cm-1 ; δH (CDCl3 /CD3OH) 1.55 (9H, s), 1.65-2.25 (4H, m), 3.32 and 3.40 (2H, ABq, J 17.6 Hz), 3.8-4.0 (2H, m), 5.08 (1H, d, J 4.8 Hz), 5.13 (1H, dd, J 7.0, 8.1 Hz), 5.91 (1H, d, J 4.5 Hz), 6.56 (1H, s), 7.2-7.5 (30H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (1002)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:11]([CH3:13])C)[C:9]#[N:10].[CH2:14]([O:16][CH:17]([O:21]CC)[CH2:18][CH2:19]Cl)C.[NH2-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:13][CH3:14])[C:9]#[N:10].[CH2:1]=[CH:2][CH2:19][CH2:18][C:17]([OH:16])=[O:21]
Reactant: CCOC(CCCl)OCC
Reactant: Cc1ccccc1C(C#N)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCC(=O)O
Product: CCCC(C#N)c1ccccc1C
Reaction time: 6 h

Procedure:
To a boiling solution of 2-(2-methylphenyl)-3-methylbutyronitrile (Herz W., J.Am.Chem.Soc. 80, 3139, 1958) (207.9 g) and 86% 3,3-diethoxypropylchloride (154 g) in anhydrous toluene (1250 ml) is dropped during about 50 minutes under stirring 107.7 g of a 50% toluenic sodium amide suspension (NaNH2 content 53.8 g) and the mixture is refluxed under continuous stirring for 6 hours. On subsequent cooling, the stirred mixture is diluted with water (300 ml), the toluenic portion is separated and the aqueous phase is extracted with toluene. The organic solutions are combined, washed with water and saturated brine (aqueous sodium chloride solution) until the reaction is neutral, and then it is dried over anhydrous sodium sulfate. Finally, the solvent is evaporated under reduced pressure and the residue is distilled to give 302.9 g (83.2%) of 5,5-diethoxy-2-isopropyl-2-(2-methylphenyl-valeronitrile, b.p. 102° to 104° C. at 4 Pa.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CS(O[CH2:11][CH:12]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])(=O)=O>>[ClH:21].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH:12]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CS(=O)(=O)OCC(CCc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Product: Cl
Product: Clc1ccc(CCC(Cn2cncn2)c2ccc(Cl)cc2Cl)c(Cl)c1

Procedure:
mp. 158.7° C., by the reaction of 1H-1,2,4-triazole with 2,4-bis(2,4-dichlorophenyl)butyl methanesulfonate.
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=[O:32].[Na+]>O.CC#N>[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([C:29]([OH:32])=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C=O)o1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of NaClO2 (2.8 mmol) in 3 mL water was added dropwise to a stirred solution of 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde (798 mg, 2.22 mmol) from step (a) in 3 mL MeCN, with cooling in an ice bath. After 2.5 h, the ice bath was removed, 2 mL more MeCN was added, and the two-phase liquid reaction mixture was stirred at room temperature for 25 h. The reaction mixture was diluted with water, made basic with saturated NaHCO3, and extracted with ethyl acetate (3×50 mL). The separated aqueous solution was acidified to pH 2 with 5% aqueous HCl and extracted with ethyl acetate (3×50 mL). This second ethyl acetate solution was washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness under vacuum to give the carboxylic acid (287 mg, 34%) which was used in the next step without further purification. The compound can be activated and esterified direct to a drug or from modified as described below.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C>C(OCC)C>[CH:1]1([Li:5])[C:10]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[CH:2]1
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 2 h

Procedure:
18.8 ml (30.0 mmol) of a 1.60 molar solution of n-butyllithium in n-hexane are added dropwise at room temperature to a solution of 30.0 mmol of the appropriately substituted indene in 150 ml of diethyl ether. The mixture is stirred at this temperature for two hours. The solvent is removed in an oil pump vacuum and the residue is suspended overnight in 100 ml of pentane. The suspension is filtered through a frit and the residue is washed with a little pentane. The product is dried in an oil pump vacuum.
Reaction SMILES: [Li][CH2:2]CCC.CN(CCN(C)C)C.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1.[OH2:22]>CCOCC>[Cl:14][C:15]1[C:16]([CH:2]=[O:22])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: [Li]CCCC
Reactant: O
Reactant: Cc1cncc(Cl)c1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: Cc1cnc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
At −78° C., under N2, BuLi (2.5 M in hexanes, 0.80 mL, 2.0 mmol) was added to a solution of TMEDA (0.30 mL, 2.0 mmol) in dry Et2O (20 mL). After addition the mixture was warmed to room temperature. After stirred at room temperature for 30 min the mixture was cooled to −78° C., and added to a solution of 3-chloro-5-methyl-pyridine (0.255 g, 2.00 mmol) (Bushby et al. J. Chem. Soc. Perkin Trans. I 1978, 1578) in dry Et2O (10 mL) pre-cooled at −78° C. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature for 1 h. Water (15 mL) was added, and the mixture was extracted with Et2O (3×40 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2) to afford 3-chloro-5-methyl-pyridine-2-carbaldehyde (0.096 g, 31%). 1H NMR (CDCl3) δ 2.44 (s, 3H), 7.65 (s, 1H), 8.54 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][C:18]=1[F:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[F:40][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To tert-Butyl 3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate (119 mg, 0.176 mmol) in THF (2 mL) at rt was added tetrabutylammonium fluoride (260 μL, 0.264 mmol, 1 M in THF). After stirring at rt for 30 min, the reaction was diluted with ethyl acetate (20 mL), washed with water followed by brine (10 mL each), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5% MeOH/EtOAc) to give the title compound (66 mg, 66%) as a yellow oil. 1H NMR (CD3OD) δ 8.62 (dd, 1H, J=7.2, 2 Hz), 8.04 (d, 1H, J=6 Hz), 7.94-7.90 (m, 2H), 7.50-7.46 (m, 2H), 7.33-7.25 (m, 3H), 7.20 (t, 1H, J=8.8 Hz), 6.67 (t, 1H, J=6.8 Hz), 6.40 (d, 1H, J=5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS(ESI+) m/z 565.17 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCCC.BrCC1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](C3C=CC=CC=3OC)[CH:36]=2)[NH:31]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>C(S)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: CCCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 20 μL of 1-propanethiol reacted to give 13 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][F:40])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCO)c1=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCF)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
50 mg (0.10 mmol) of 2-[3-(4-chlorophenyl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 396 are dissolved in 1.5 ml of dichloromethane and treated at −10° C. with 20.5 μl (0.155 mmol) of diethylaminosulphur trifluoride. This is warmed to RT within 1 hr. Next, the reaction solution is treated with 5 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 37 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][CH:16]4[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][N:18]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17]4)=[O:14])=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:27][S:24]([N:18]1[CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH:16]([NH:15][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[NH:10][CH:11]=2)=[O:14])[CH2:17]1)(=[O:26])=[O:25]
Reactant: CC1(C)CCN(S(C)(=O)=O)CC1NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC1(C)CCN(S(C)(=O)=O)CC1NC(=O)c1c[nH]c2ncc(C3CC3)nc12
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of 2-cyclopropyl-N-(4,4-dimethyl-1-(methylsulfonyl)piperidin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (143 mg, 0.27 mmol) in CH2Cl2 (5 mL) was added TFA (2.0 mL, 26.0 mmol). The yellow reaction mixture was stirred for 3 h then concentrated The residue was redissolved in CH2Cl2 (5 mL) and ethylenediamine (0.5 mL, 7.4 mmol) was added. The reaction mixture was stirred at for 1 h then concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc) to isolate 66 mg (62%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-4,4-dimethyl-piperidin-3-yl)-amide as a white solid. MS: (M+H)+=392.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH3:3].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=O.Cl.[C:34]([C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)(=[NH:36])[NH2:35].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]2[C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[C:8]([CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[NH:36][C:34]([C:37]3[O:38][CH:39]=[CH:40][CH:41]=3)=[N:35]2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N=C(N)c1ccco1
Reactant: CN(C)CCOCC(=O)CC(=O)OCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCC1=C(C(=O)OCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccco2)N1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(N,N-dimethylamino)ethoxy)acetoacetate (2.85 g, 9.27 mmol), 3,4-dichlorobenzaldehyde (1.62 g, 9.27 mmol), 2-amidinofuran hydrochloride (1.36 g, 9.27 mmol) and sodium hydrogen carbonate (0.78 g, 9.27 mmol) was stirred in N,N-dimethylformamide (15 mL) for 3 days at room temperature and then heated to 60° C. for 7 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (578.3 mg) as an oil. Electrospray MS m/z 556/558 [M+H]+.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][C@@:13]12[C@@:21]([OH:26])([C:22]([CH2:24][OH:25])=[O:23])[C@H:20]([OH:27])[CH2:19][C@H:18]1[C@@H:17]1[CH2:28][CH2:29][C:30]3[C@@:36]([CH3:37])([C@H:16]1[C@@H:15]([OH:38])[CH2:14]2)[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3.C(=O)CCC>C(#N)C>[CH3:6][CH2:1][CH2:2][CH:3]1[O:26][C@:21]2([C:22]([CH2:24][OH:25])=[O:23])[C@@H:20]([CH2:19][C@@H:18]3[C@:13]2([CH3:12])[CH2:14][C@H:15]([OH:38])[C@H:16]2[C@H:17]3[CH2:28][CH2:29][C:30]3[C@:36]2([CH3:37])[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3)[O:27]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Solvent: CC#N
Solvent: CCCC=O
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
The reaction is carried out in a nitrogen atmosphere. 15,4 g p-toluenesulphonic acid is dissolved into 200 ml acetonitrile. To the solution 50,0 g 16α-hydroxyprednisolone and 17.6 ml butanal are added. The temperature rises to 25° C. After 30 min most of the material is dissolved. Shortly thereafter the product starts to crystallize. After 3 hours the reaction is stopped by the addition of 75 ml aqueous saturated sodium hydrogen carbonate solution, whereupon the product crystallizes. The dried product is dissolved in methylene chloride and methanol and is crystallized by the addition of ligroine (b.p. 40-65) giving crude budesonide.