Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]Cl.C(NC1C(Cl)=CC(C(=O)CCCCCl)=C(O)C=1)(=O)C.[C:32]([NH:35][C:36]1[C:41]([Br:42])=[CH:40][C:39]([C:43](=[O:49])[CH2:44][CH2:45][CH2:46][CH2:47][Br:48])=[C:38]([OH:50])[CH:37]=1)(=[O:34])[CH3:33]>>[C:32]([NH:35][C:36]1[C:41]([Br:42])=[CH:40][C:39]([C:43](=[O:49])[CH2:44][CH2:45][CH2:46][CH2:47][Br:48])=[C:38]([O:50][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:37]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cc(O)c(C(=O)CCCCBr)cc1Br
Reactant: COc1cc(CCl)cc(OC)c1
Agent: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Product: COc1cc(COc2cc(NC(C)=O)c(Br)cc2C(=O)CCCCBr)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (b), but replacing iodomethane with 3,5-dimethoxybenzylchloride and 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one with 1-(4-acetylamino-5-bromo-2-hydroxyphenyl)-5-bromo-pentan-1-one, gave 1-[4-acetylamino-5-bromo-2-(3,5-dimethoxybenzyloxy)phenyl]-5-bromopentan-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:18]([N:20]1[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:35][CH2:36][CH2:37][Cl:38])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:18]([N:20]1[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(O)cnc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCCCCl)cnc21
Yield: 63 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 2-(4,4-difluoro-piperidine-1-carbonyl)-5-hydroxy-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester, potassium carbonate and 1-bromo-3-chloropropane in 2-butanone to give the desired product as a colorless foam (63%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of methyl 4-bromobutyrate (1.5 g, 8.29 mmol), 4-chlorophenol (1.17 g, 9.11 mmol), potassium carbonate (2.86 g, 20.7 mmol), and anhydrous N,N-dimethylformamide (5 mL) was added to a 25 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at room temperature for 16 hours. Progress of the reaction was monitored by analytical HPLC with UV detection (Rt=6.5 min). The mixture was added to stirring ice/water (150 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaCl (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexanes to afford the title compound as a clear oil (1.45 g, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32](OC)=O)=[CH:25][C:24]=2[O:23]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]3[NH:21][C:19](=[O:20])[C:3]4[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)=[CH:25][C:24]=2[O:23]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 26.8 %

Procedure:
10 mg (0.034 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.103 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4 mg (48%) of a solid, Rf=0.68 (dichloromethane/methanol=15:1).
Reaction SMILES: N1C=CC=C(NC(=S)OC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CCC=C(C)C)C=1.[CH2:31]([CH2:41]/[C:42](/[CH3:51])=[CH:43]/[CH2:44][CH2:45]/[C:46](/[CH3:50])=[CH:47]/[CH2:48][OH:49])/[CH:32]=[C:33](/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])\[CH3:34].[N:52]1[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[O:60])=[CH:54][CH:53]=1>>[N:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59](=[O:60])[O:49][CH2:48]/[CH:47]=[C:46](\[CH3:50])/[CH2:45][CH2:44]/[CH:43]=[C:42](\[CH3:51])/[CH2:41][CH2:31]/[CH:32]=[C:33](\[CH3:34])/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])=[CH:54][CH:53]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C=Nc1ccncc1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=O)Nc1ccncc1
Yield: 3 %

Procedure:
Similar to the preparation of 38a, the reaction of alcohol 1 with 4-pyridyl isocyanate afforded the desired compound 39 in 3% yield (10 mg) as a viscous oil. Column (DCM/MeOH); TLC Rf: 0.34 (10% MeOH/DCM); LCMS: MS (m/z): 411 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:15].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([NH:20][C:10](=[O:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[CH:5]=1)([CH3:14])[CH3:13])[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc(C(C)(C)C(=O)O)cc1C
Reactant: CC(C)CN
Product: COc1ccc(C(C)(C)C(=O)NCC(C)C)cc1C
Yield: 64 %

Procedure:
Prepared in a similar manner to Example 35a starting from 2-(4-methoxy-3-methylphenyl)-2-methylpropanoic acid (example 50d) and isobutylamine. Yield: 64%. MS+H (264).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccccc2C(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 91 mg (0.55 mmol) of 2-hydroxy-benzotrifluoride and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue purified by column chromatography (50 g silica gel; diethyl ether/heptane 1:1) to yield 172 mg (70%) product as a white solid. MS (ISP) 495.5 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH2:45]([N:47]([CH2:51][CH3:52])[C:48](Cl)=[O:49])[CH3:46]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:48](=[O:49])[N:47]([CH2:51][CH3:52])[CH2:45][CH3:46])=[CH:31][CH:30]=1)#[N:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (40 mg, 0.29 mmol) followed by diethylcarbamoyl chloride (20 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 141 as a white solid (35 mg, 67%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.01 (m, 1H), 1.00 (d, 3H, J=5.7 Hz), 1.10-1.18 (m, 7H), 1.50-1.58 (m, 1H), 1.70-1.73 (m, 3H), 2.14 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=11.4 Hz), 2.73-2.88 (m, 3H), 3.15-3.36 (m, 5H), 3.50-3.56 (m, 1H), 3.74 (s, 2H), 3.87-3.93 (m, 1H), 6.51 (d, 2H, J=7.2 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.95-6.99 (m, 3H), 7.41-7.50 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.80, 14.59, 19.53, 29.33, 30.74, 31.32, 36.87, 40.26, 42.17, 42.56, 43.96, 48.78, 52.59, 57.57, 60.99, 112.84, 114.95, 119.36, 122.75, 127.68, 128.77, 129.55, 130.48, 130.83, 131.43, 134.47, 139.03, 142.64, 143.52, 146.07, 155.18, 170.24. ES-MS m/z 610 (M+H). Anal. Calcd. for C37H47N5O3.0.8H2O: C, 71.19; H, 7.85; N, 11.22. Found. C, 71.09; H, 7.68; N, 11.16.
Reaction SMILES: [CH2:1]([C:5]1([CH2:22][CH2:23][CH2:24][CH:25]=C)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1([C:19]([CH3:21])=[CH2:20])[OH:18])[CH2:2][CH2:3]C>ClCCl>[CH2:22]([C:5]12[CH2:1][CH2:2][CH2:3][CH:21]=[C:19]([CH3:20])[C:6]1([OH:18])[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:23][CH2:24][CH3:25]
Reactant: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1(O)C(=C)C
Solvent: ClCCl
Product: CCCCC12CCCC=C(C)C1(O)c1ccc(OCOC)cc1C2
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 2-butyl-1-isopropenyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanol (200 mg, 0.56 mmol) in dichloromethane (22 mL) was treated with tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine ruthenium(IV) dichloride (47 mg, 0.056 mmol). After stirring at 45° C. overnight, the mixture was treated with additional tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine ruthenium (IV) dichloride (47 mg, 0.056 mmol) and stirred at 45° C. for another 24 hours. The mixture was concentrated and the residue purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with 10% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-4b(7H)-ol as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[CH2:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)=[O:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][CH2:18][CH2:19][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH3:22])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(CCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (Example 49A) and 4-bromoacetanilide: MS (APCI) m/z 432 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[OH:12])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Reaction time: 6 h
Yield: 90.1 %

Procedure:
192.0 g (1 mol) of 2,4-dichloronitrobenzene, 600 g of water and 273.0 g (2.05 mol) of sodium hydroxide are heated to 140° C. in a VA steel autoclave with vigorous stirring for 6 hours. The reacted reaction mixture is removed from the autoclave at 70° C. The orange-brown solution produced is adjusted to pH 2 using 30% strength hydrochloric acid, and the product is distilled over using steam. On stirring the distillate (about 1.5 1) at 10° C, 2-nitro-5-chlorophenol (156.4 g, 90% of theory) is obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:6]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)CCC(F)(F)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCC(F)(F)Cl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g of 4-chloro-4,4-difluoro-butyric acid chloride are added dropwise at 0° over a period of half an hour to a solution of 2.13 g of 2-aminopyridine and 4.47 g of pyridine in 50 ml of toluene. The reaction mixture is stirred for 16 hours at room temperature, diluted with 150 ml of diethyl ether, washed in succession with saturated NaHCO3 solution and saturated NaCl solution, dried over MgSO4, and concentrated by evaporation. The residue is recrystallised from toluene/hexane to give the title compound which melts at 64°-65°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1([C:29]#[N:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:29]([C:26]1([NH:25][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])[CH2:28][CH2:27]1)#[N:30]
Reactant: N#CC1(N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C#N)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (90 mg, 0.29 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (41 mg, 0.348 mmol), EDCI (110 mg, 0.58 mmol) and DMAP (75 mg, 0.58 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give the crude product which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 23%) as a white solid. MS: (M+H)+=376; 1H NMR (300 MHz, DMSO): δ 12.95 (s, 1H), 9.10 (s, 1H), 8.87 (s, 1H), 8.56-8.53 (m, 2H), 6.69 (d, 1H, J=8.7 Hz), 7.26 (t, 1H, J=8.7 Hz), 4.15 (s, 3H), 1.70 (brs, 2H), 1.64 (brs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OC)(OC)(OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(C)(OC)OC
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Yield: 10 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (1.0 g, 3 mmol) and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic acid (250 mg) in acetonotrile (10 mL) was heated to reflux for 7 days. The suspension was filtered and washed with ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (108 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% F3PO4, 5.17 min (98.7%); mp: 273-275° C.; 1H NMR (DMSO-d6) δ 2.14-2.27 (m, 1H, CHH), 2.56-2.69 (m, 2H, 2CHH), 2.64 (s, 3H, CH3), 2.72-2.90 (m, 1H, CHH), 5.29 (dd. J=6, 11 Hz, 1H, NCH), 7.58 (d, J=9 Hz, 1H, Ar), 7.98 (dd, J=2, 9 Hz, 1H, Ar), 8.12 (d, J=2 Hz, 1H, Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95, 137.51, 145.76, 155.74, 159.32, 167.24, 172.49; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 48.02; H, 3.18; N, 11.76.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]([CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=2)[CH2:15]1)=[N+:11]=[N-:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:54]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])(=[O:57])[NH:55][NH2:56]>CN(C=O)C>[C:59]([O:58][C:54]([NH:55][NH:56][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][C:20]([N:16]2[CH2:15][C@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:18][C:17]2=[O:19])=[CH:21][C:22]=1[F:29])=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: CC(C)(C)OC(=O)NN
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Diisopropylethylamine (4.67 ml, 0.0268 mol) is added to a mixture of 4-(5(R)-Azidomethyl-2-oxo-oxazolidin-3-yl)-2-fluorobenzoic acid (2.50 g, 0.00892 mol) [prepared according to the procedure described in U.S. Pat. No. 6,239,152] and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.73 g, 0.00981 mol) in DMF (30 ml) and stirred for 20 minutes at room temperature. tert-Butyl carbazate (1.30 g, 0.00981 mol) is then added and the mixture stirred at room temperature overnight. The reaction mixture is evaporated under vacuum and the residue diluted with water. The resulting precipitate is filtered and dried under vacuum to give product as a white solid (3.52 g, 99%); 1HNMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.72-3.76 (m, 2H), 3.81 (dd, J=6.0, 9.3 Hz, 1H), 4.17 (t, J=9.1 Hz, 1H), 4.88-4.96 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.57 (dd, J=2.2, 13.2, 1H), 7.66 (t, J=8.2, 1H), 8.96 (s, 1H), 9.92 (s, 1H); Rf(EtOAc)=0.54; mp 173-5.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[CH:7]=1)(=[O:5])=[O:4].N([O-])=[O:14].[Na+].NC(N)=O>O.OS(O)(=O)=O>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccc(N)c1
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CNS(=O)(=O)c1cccc(O)c1
Reaction time: 0.17 h

Procedure:
N-Methyl-3-aminobenzene sulfonamide (488 mg, 2.62 mmole) was dissolved in a mixture of 10 mL of H2O and 2 mL of conc. H2SO4, and was cooled to −5°. A solution of NaNO2 (207 mg, 3 mmole) in 2 mL of H2O was added dropwise at such a rate that the temperature doesn't exceed 0°. The reaction was stirred for 10 minutes, urea (100 mg) was added, and the reaction was stirred an additional 10 minutes. The cold solution of diazo compound was slowly added with stirring to a 0° solution of Cu(NO3)2 dihydrate (10.3 g, 43 mmole) and Cu2O (363 mg) in 100 mL of H2O. Stirring was continued for 30 minutes as the temperature was allowed to warm to 23°. The heterogeneous reaction was extracted with Et2O, and the extracts were extracted with 0.2N NaOH. The basic extracts were washed with Et2O, acidified, and extracted with CH2Cl2. The extracts were dried, and the solvent removed. The residue was chromatographed on a silica gel column, and elution with 50% EtOAc in hexane gave the titled product, 175 mg (36%). MS (ESI) 188 (MH+).
Reaction SMILES: [CH2:1]([N:15]([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])S(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].CO.O>O1CCCC1>[CH2:26]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[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]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of N,N-ditetradecyl-p-toluenesulfonamide (4.16 g; 7.38 mmol) in tetrahydrofuran (2 ml) is added at 0° C. to a solution of lithium naphthalenide [prepared from naphthalene (4.73 g; 36.88 mmol) and lithium metal (0.38 g; 55.35 mmol) in tetrahydrofuran (40 ml) at room temperature for 1 h] and the reaction mixture is stirred for 1 h at room temperature. Methanol (2 ml) is added, followed by water (25 ml) and the mixture is extracted with ether (2×25 ml). The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid which is purified by chromatography on a column of silica gel (eluent: ether) to give ditetradecylamine (2.68 g; 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16](I)[C:15]([CH3:20])=[N:14]1.[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C)C=O.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([CH:21]=[CH2:22])[C:15]([CH3:20])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(C)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3,5-dimethyl4-iodopyrazole (1 g) in dimethylformamide (10 ml) containing yinyltri-n-butyltin (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) was stirred at 75° C. for 2 hours then left overnight at room temperature. The mixture was again heated at 75° C. for 2 hours then vinyltri-n-butyltin (2 ml) was added and the mixture heated at 75° C. for 2 hours. Tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added and heating continued for a further 2 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water (×2), then brine, dried (Na2SO4) and evaporated. The residue was adsorbed onto silica gel (20 g) and purified by column chromatography on silica gel (150 g) eluted with hexane, then hexane with increasing amounts of dichloromethane and finally dichloromethane. Combination and evaporation of suitable fractions provided the title compound as yellow oil.