Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Br[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10])[CH3:2]
Reactant: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cc(C#N)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1M solution of ethyl magnesium bromide (2 mL, 1.5 equiv), THF (10 mL) was added and the reaction mixture was cooled down to 0° C. A solution of 0.5 M in THF of zinc dichloride (4 mL, 1.5 equiv) was added slowly and the reaction mixture was stirred for 30 min at the same temperature. Pd(tBu3P)2 (102 mg, 0.1 equiv) was added followed by the addition of a solution of 3-bromo-4-[(phenylmethyl)oxy]benzonitrile (Intermediate 110, 576 mg) in THF and the reaction was allowed to reach room temperature. After stirring 30 minutes, some additional Pd(tBu3P)2 was added (51 mg, 0.05 equiv), then 30 min stirring, then third addition of Pd(tBu3P)2 (51 mg, 0.05 equiv) and stirring 30 min. The reaction mixture was quenched with an aqueous saturated solution of NH4Cl (100 mL) and extracted 3 times with ethyl acetate (3×150 mL). The gathered organic phases were filtrated on celite, dried over sodium sulphate. The residue obtained was purified by chromatography on silica gel (Companion system, 40 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate 100:0, then 100:0 to 90:10. Evaporation afforded the title compound (336 mg) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
62 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50 mg, 0.195 mmol), 1-(4-methoxyphenyl)piperazine (49 mg, 0.186 mmol), DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)3 (118 mg, 0.558 mmol).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[O:20]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][C:24]5([O:23][CH2:22][CH2:21][O:20]5)[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CC2(CN1)OCCO2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC4(C3)OCCO4)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 11 with 1,4-dioxa-7-azaspiro[4.4]nonane to give 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 229°-230°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:30])[C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(F)cc1Oc1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 377B (0.750 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.091 g). The reaction was stirred for 30 minutes at room temperature and then iodomethane (0.142 mL) was added to the reaction and stirring was continued at room temperature for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate (75 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 5-15% ethyl acetate/hexanes over 30 minutes (flow=40 ml/min) to provide the title compound.
Reaction SMILES: [Cl:1]C1C=C(C=C(Cl)C=1)C(C)=C.S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20](O)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20]([Cl:1])=[O:21]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(C)c1cc(Cl)cc(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1

Procedure:
It has been known that 3,5-dichloro-α-methylstyrene can be produced by reacting thionyl chloride with 3,5-dichlorobenzoic acid to obtain 3,5-dichlorobenzoyl chloride and then reacting methanol with 3,5-dichlorobenzoyl chloride to obtain methyl-3,5-dichlorobenzoate and reacting methylmagnesium chloride with methyl-3,5-dichlorobenzoate in ether and then, hydrolyzing the product with a diluted hydrochloric acid and dehydrating the product over sodium bisulfate, in for example, Journal of the American Chemical Society 73 January 1951, page 455-456. However, this process is not advantageous as an industrial process because many reaction steps are needed for producing methyl3,5-dichlorobenzoate and a complicated reaction step is included in these steps for producing the starting material and the hydrolysis and the dehydration should be separately carried out.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:52]([CH3:54])[CH3:53])[C:10]([O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[S:36][C:35]4[C:30](=[N:31][CH:32]=[CH:33][C:34]=4[O:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][CH:48]5[CH2:50][CH2:49]5)=[O:46])=[CH:40][C:39]=4[F:51])[CH:29]=3)=[CH:26][CH:27]=2)[CH2:17][CH2:16]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:52]([CH3:54])[CH3:53])[C:10]([O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[S:36][C:35]4[C:30](=[N:31][CH:32]=[CH:33][C:34]=4[O:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][CH:48]5[CH2:49][CH2:50]5)=[O:46])=[CH:40][C:39]=4[F:51])[CH:29]=3)=[CH:26][CH:27]=2)[CH2:17][CH2:16]1)=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)OCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Yield: 33.3 %

Procedure:
A solution of 78 (115 mg. 0.15 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at RT for 3 h. The TFA was removed by co-evaporation with DCM, diluted with a minimum of water, and the pH was adjusted to around 9 with a saturated aqueous solution of sodium bicarbonate (and few drops of 1N NaOH at the end). The aqueous solution was extracted with DCM containing traces of methanol. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 10 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 20/80 over 20 CV), to afford the title compound 79 (36 mg, 0.05 mmol, 36% yield) as a white sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.4, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=10.4 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 6.58 (bd, J=2.2 Hz, 1H), 4.26-4.18 (m, 1H), 4.11-4.03 (m, 1H), 3.54 (s, 2H), 3.10 (d, J=5.3 Hz, 1H), 2.59-2.30 (m, 11H), 1.88-1.78 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H), NH2 is missing. MS (m/z): 662.7 (M+H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[O:9][C:8]([C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:25][C:26](=[O:47])[C@H:27]([O:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[C:32]([S:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])[N:31]=1)[CH3:28])[CH3:24]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([NH:12][C:10]([C:8]1[O:9][C:5]([S:2]([NH:1][C:34]2[N:33]=[C:32]([S:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[F:46])[N:31]=[C:30]([O:29][C@H:27]([CH3:28])[C:26]([O:25][CH2:23][CH3:24])=[O:47])[CH:35]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)NC(=O)c1ccc(S(N)(=O)=O)o1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 5-(aminosulfonyl)-N-(tert-butyl)-2-furamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (58 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-diphenyl (XPHOS) (30 mg), cesium carbonate (0.65 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (product of Example 11 step i) (0.26 g) in dioxane (10 mL). Purification was trituration with Et2O to give the subtitle compound as a white solid. Yield: 0.25 g
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].[H-].[Na+]>>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][CH:8]([C:7](=[O:16])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[CH3:18]
Reactant: O=C(CC(=O)c1ccco1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccco1

Procedure:
Following a procedure analogous to that set out in Example 49, 40 grams 1-phenyl-3-(2-furyl)-1,3-propanedione were alkylated by reaction with 36 grams bromoacetic acid-ethyl ester and 23 grams of a 20% suspension of sodium hydride in paraffin oil to form 3-benzoyl-3-(2-furoyl)-propionic acid-ethyl ester, which was further reacted with 28 grams phenylhyrazine in glacial acetic acid to form the respective pyrazol-4-acetic acid-ethyl esters, which without being separated, were saponified in accordance with a procedure analogous to that described in Example (1b).
Reaction SMILES: [H][H].C(=O)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH:18]1[N:22]([C@@H:23]2[O:27][C@@H:26]3[CH2:28][O:29][P:30]([OH:33])([O:32][C@H:25]3[C@H:24]2[OH:34])=[O:31])[C:21]2[NH:35][C:36]([NH2:40])=[N:37][C:38](=[O:39])[C:20]=2[N:19]=1>>[CH:23]([NH2:22])=[O:27].[CH:18]1[N:22]([C@@H:23]2[O:27][C@@H:26]3[CH2:28][O:29][P:30]([OH:33])([O:32][C@H:25]3[C@H:24]2[OH:34])=[O:31])[C:21]2[NH:35][C:36]([NH2:40])=[N:37][C:38](=[O:39])[C:20]=2[N:19]=1
Reactant: [H][H]
Agent: CC=O
Agent: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Product: NC=O

Procedure:
Hydrogen abstraction from the carbonyl carbon of aldehydes by a radical source was utilized to yield the acyl radical, a highly reactive acylating agent, for the synthesis of 8-acyl-cGMP derivatives. Acetaldehyde and cGMP, in the presence of t-BuOOH, FeSO4 and 0.3 N H2SO4, yielded 8-acetylguanosine 3',5'-cyclic phosphate (6); however, in initial experiments a significant amount of 8-methyl-cGMP (2) was also formed. To avoid the possibility of methylation competing with hydrogen abstraction from the aldehyde, ammonium persulfate was subsequently used as a radical source. In this manner, 6 was readily obtained in 43% yield. Using the appropriate aldehyde under these conditions, 8-n-butyryl (7), 8-isobutyryl (8), and 8-benzoylguanosine 3',5'-cyclic phosphate (9) were prepared from cGMP. Formamide and cGMP under these conditions gave 8-carbamoylguanosine 3',5'-cyclic phosphate (10).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([F:11])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:63][C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[C:53]4[C:48]=3[CH:47]=[CH:46][NH:45]4)[CH:62]=[C:61]3[C:57]=2[CH:58]=[N:59][NH:60]3)=[O:10])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(Cl)ccc1F
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
6-Chloro-3-fluoro-2-pyridinecarboxylic acid (available from Asymchem, 848 mg, 4.83 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1838 mg, 4.83 mmol) were dissolved in DMF (15 ml) and DIPEA (2.53 ml) was added. The mixture was stirred at room temperature for 30 mins. 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.42 mmol) was added and the mixture was stirred at room temperature for 36 h. Some solvent was removed in vacuo to give ˜5 ml which was added to 2×50 g aminopropyl cartridges which had been preconditioned with methanol. The reaction mixture remained on the cartridges for 2 h before being eluted with methanol. Some solvent was removed in vacuo and a yellow precipitate crashed out which was filtered off to give the title compound (531 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.4 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:3]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 71 %

Procedure:
A mixture of 2-bromo-6-methyl-5-nitropyridine (ECA International Corporation, Palatine, Ill., USA; 2 g, 9.2 mmol), 1,2,4-triazole (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 0.64 g, 9.2 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in dimethylsulfoxide (4 mL) was stirred at room temperature for 1.5 days and then poured into a mixture of ice and water (400 mL). The resulting mixture was stirred until all of the ice melted to give a dark purple slurry. The solid was filtered off to give 2-methyl-3-nitro-6-[1,2,4]triazol-1-yl-pyridine (1.34 g, 71%) as a purple solid with a purity estimated at 93% by LC-MS. This was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[CH:13]2>C1COCC1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH2:19][CH:20]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH:2]4[C:1](=[O:7])[NH:5][C:4](=[O:6])[CH:3]4[C:13]=3[C:12]=2[CH:11]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2[nH]c(/C=C/C(=O)OCc3ccccc3)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(C(=O)OCc1ccccc1)C3
Temperature: 25 °C
Yield: 83 %

Procedure:
Maleimide (4.82 g, 0.050 mol) was added to a solution of benzyl (2E)-3-(5-methoxy-1H-indol-2-yl)-2-propenoate, (12.71 g, 0.041 mol) prepared as in example 1 in THF (150 mL) in a 250 mL flat-bottomed flask and the mixture was stirred until homogeneous. The THF was removed in vacuo and the residue dried under high vacuum for 30 min. The flask was immersed in a 175° C. oil bath and the mixture was stirred at this temperature for 3 h. The solid melt was cooled to room temperature and ethyl acetate (100 mL) was added. The solid mass was partially broken up with a spatula and the mixture was stirred vigorously overnight, after which time the product (3) was present as a cream precipitate. Filtration followed by washing with diethyl ether gave benzyl 9-methoxy-1,3-dioxo-1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 83%), mp 179–181° C. 1H NMR δ [(CD3)2SO] 10.98 (br s, 1H), 10.87 (s, 1H), 7.45–7.32 (m, 5H), 7.20 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.69 (dd, J=8.7, 2.4 Hz, 1H), 5.21 (s, 1H), 4.22 (br d, J=7.8 Hz, 1H), 4.14 (dd, J=7.8, 4.2 Hz, 1H), 3.75 (s, 3H), 3.19–3.13 (m, 1H), 3.00 (dd, J=16.5, 4.8 Hz, 1H), 2.79–2.70 (m, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[NH:20])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.CN(C)/[CH:24]=[CH:25]/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>COCCO>[CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:21]=[C:26]([C:28]4[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=4)[CH:25]=[CH:24][N:20]=3)=[CH:16][CH:17]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Solvent: COCCO
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCC[C@@H]4C(=O)NC4CC4)cc3)n2)n1C(C)C
Temperature: 200 °C
Yield: 36 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 63; 0.29 g, 1.0 mmol) and ((2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 0.15 g, 0.68 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (110 mg, 36%). NMR (299.954 MHz, CDCl3) 8.28 (d, 1H), 7.39 (d, 1H), 7.34 (s, 1H), 6.85-6.82 (m, 2H), 6.60-6.57 (m, 3H), 5.61 (septet, 1H), 3.96-3.92 (m, 1H), 3.62 (t, 1H), 3.19 (q, 1H), 2.76-2.67 (m, 1H), 2.56 (s, 3H), 2.30-2.22 (m, 2H), 2.07-1.84 (m, 2H), 1.47 (d, 6H), 0.78-0.70 (m, 2H), 0.45-0.38 (m, 2H); m/z 446.
Reaction SMILES: [Na+].[CH3:2][C:3]([C:11]1[CH:12]=[C:13]([S:17]([O-:20])(=O)=[O:18])[CH:14]=[CH:15][CH:16]=1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:23])=O.C>CN(C=O)C.CCCCCC>[CH3:2][C:3]([C:11]1[CH:12]=[C:13]([S:17]([Cl:23])(=[O:20])=[O:18])[CH:14]=[CH:15][CH:16]=1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
3-(α,α-Dimethylbenzyl)benzenesulphonic acid sodium salt (9.6 g) is dissolved in DMF (16 ml) and cooled to 10° C. Thionyl chloride (12ml) is added dropwise maintaining the temperature below 20° C. The mixture is allowed to warm to room temperature and stirred one hour. The solution is poured onto ice/water (100 ml) and the mixture is extracted with ether (3×8 ml). The combined extracts are dried (MgSO4) and the solvent evaporated to give pale yellow waxy crystals which are dissolved in hexane (200 ml) and decolourised (charcoal). Evaporation produces white crystals of 3-(α,α-dimethylbenzyl)benzenesulphonyl chloride which are dried at room temperature under vacuum, m.p. 47.5°-49° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[CH2:11].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 18.4 g. (0.1 mole) of cyanuric chloride in 150 ml. of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g. (0.1 mole) of 4-vinylaniline and 12.9 g. (0.1 mole) of N,N-di-iso-propylethylamine. After the addition was complete, the solution was stirred at room temperature for 15 min., and then poured into 1 liter of ice water to isolate the product. The product was collected by filtration, washed with 200 ml. of water, and dried in vacuo at room temperature to give 25 g. Recrystallization from 75 ml. of benzene gave 15.0 g. (56%) (mp 152°-154°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.[NH2:21][CH:22]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:20])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: NC(CO)c1cccnc1
Product: O=C(NC(CO)c1cccnc1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 1 (see Example 1.1) and 2-amino-2-(pyridin-3-yl)ethanol. LCMS m/z=397.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.48 (td, J=4.7 and 3.5 Hz, 1H), 1.17 (td, J=7.9 and 4.7 Hz, 1H), 2.08-2.14 (m, 1H), 2.23-2.30 (m, 1H), 2.56 (bs, 1H), 2.93 (d, J=16.4 Hz, 1H), 3.03 (dd, J=16.4 and 6.2 Hz, 1H), 3.98-4.03 (m, 2H), 5.19-5.24 (m, 1H), 7.02 (t, J=8.0 Hz, 2H), 7.27 (dd, J=7.8 and 5.0 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.60-7.67 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.53 (bs, 1H), 8.66 (bs, 1H).