Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:8]4[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Product: Cn1c2ccc(Cl)cc2c2c3ccccc3c(OCCN3CCOCC3)nc21

Procedure:
5-β-Morpholinoethyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 140°-142° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and β-morpholinoethyl chloride by the method described in Example 8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[N:9]=[CH:8]1.[OH-].[Na+]>CCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]([OH:18])=[O:17])[N:9]=[CH:8]1
Reactant: CCOC(=O)c1ncn(-c2ccccn2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a solution of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate (1.2 g, 4.21 mmol) in EtOH (20 mL) was added a predissolved solution of sodium hydroxide (1.00 g, 25.1 mmol) in water (5.00 mL). The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was concentrated in vacuo, acidified with dilute HCl, and extracted from 1 M HCl with EtOAc. Some product did extract but the aqueous layer remained yellow with desired product as well. The aqueous layer was brought to pH 5 using ammonium hydroxide and NH4Cl and extracted with EtOAc again which afforded additional product. The combined organic layers were dried over MgSO4, filtered, concentrated to give 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (140 mg, 0.544 mmol, 12.94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.5 (1H, br s), 8.69 (1H, dd), 8.35 (s, 1H), 8.14 (1H, dt), 7.78 (1H, d), 7.67 (1H, dt).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.O[C@@H:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[O:35][C@:34]([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)([O:43][CH3:44])[CH2:33]1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:9][C@@H:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[O:35][C@@:34]([O:43][CH3:44])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)[CH2:33]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=CCCC[C@@H]1C[C@@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a solution of benzoic acid (31.7 mg, 0.260 mmol) in dry toluene (5 mL) under a nitrogen atmosphere was added diisopropylethylamine (0.0435 mL, 0.250 mmol) and 2,4,6-trichlorobenzoyl chloride (0.0391 mL, 0.250 mmol). The mixture was stirred at room temperature for 3 h, after which the title compound from Example 14 (21.5 mg, 0.051 mmol) and DMAP (32.9 mg, 0.269 mmol) were added. This mixture was stirred at room temperature for 18 h, after which it was diluted with ether and washed with satd aq NH4Cl and brine, and the organic phase was dried and evaporated. Chromatography of the residue on silica gel, eluting with an ethyl acetate/dichloromethane gradient, afforded the title compound (21.7 mg, 81%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(F)cc3)nc21

Procedure:
Analogously to the procecure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.92 g (11.4 mmol) of methyl 4-fluorophenylacetate.
Reaction SMILES: COC1N=CC(COC2C3C(=CC=CC=3)C=CC=2C(NC(C)(C)C(O)=O)=O)=CC=1.C[O:31][C:32](=[O:60])[C:33]([NH:37][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]=1[O:50][CH2:51][C:52]1[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)=[O:39])([CH3:36])[CH2:34][CH3:35]>>[CH3:59][O:58][C:55]1[N:54]=[CH:53][C:52]([CH2:51][O:50][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:48]=[CH:49][C:40]=2[C:38]([NH:37][C:33]([CH3:36])([CH2:34][CH3:35])[C:32]([OH:60])=[O:31])=[O:39])=[CH:57][CH:56]=1
Reactant: CCC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OC)nc1)C(=O)OC
Agent: COc1ccc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cn1
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OC)nc1)C(=O)O

Procedure:
2-{[1-(6-Methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid was prepared in similar manner as 2-{[1-(6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid (example 152) via 2-{[1-(6-Methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid methyl ester (C24H26N2O5 (422.49), LCMS (ESI): 423.15 (MH+)).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[CH:20]=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[CH:20]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(OCc2nc(C(C)(C)C)cs2)c(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 140 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
A mixture of 4-tert-butyl-2-(2-formyl-4-methoxyphenoxymethyl)thiazole (3.23 g) and acetic anhydride (3.2 ml) in xylene (30 ml) was stirred at 140° C. for 14 hours. After being cooled, the resulting mixture was concentrated to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with toluene. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(5-methoxybenzofuran-2-yl)thiazole (2.40 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][NH2:9])[CH3:3].[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[CH:20]=[CH:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CCO.CO>[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:10])[CH:25]=2)[CH:20]=[CH:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCCNCc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-amino-butyric acid ethyl ester hydrochloride (1 eq.) in either MeOH or EtOH were added TEA (2.5 eq.), 6-formyl-indole-1-carboxylic acid tert-butyl ester (0.95 eq.) and MgSO4 (1.5 eq.). The reaction was stirred at 20° C. for 15 h, then cooled to −15° C. NaBH4 (2 to 6 eq.) was added portionwise. The reaction was stirred for 1 h at −15° C., then 1 h at 0° C. The reaction was quenched with the addition of cold water at 0° C. The crude was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 99/1) to afford 6-[(3-ethoxycarbonyl-propylamino)-methyl]-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.Cl[Sn]Cl.O.[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]([N+:26]([O-])=O)=[C:17]2[O:25][CH2:24][CH2:23][N:18]2[C:19](=[O:22])[C:20]=1[CH3:21].C(=O)(O)[O-]>C(O)C.C(OC(=O)C)C>[NH2:26][C:16]1[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:20]([CH3:21])[C:19](=[O:22])[N:18]2[CH2:23][CH2:24][O:25][C:17]=12
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCO2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Concentrated HCl (0.2 mL) and SnCl2.H2O (0.24 g, 1.06 mmol) were added to 7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (0.15 g, 0.347 mmol) in ethanol (5 mL). The resulting mixture was heated to reflux for 2 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was cooled to room temperature, diluted with ethylacetate, basified with saturated bicarbonate solution and filtered through celite. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 0.08 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[C:23]([O:25]C2CCCCO2)[CH:22]=[CH:21][C:3]=1[C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C2CCCCO2)=[CH:9][CH:8]=1.C(Cl)Cl.CO.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([C:3]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:2]=2[OH:1])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a mixture of 4,000 g of crude 2'-hydroxy-4,4'-bis(tetrahydropyranyloxy)chalcone (purity: 79.4%) and 13 ml of a mixed solvent of methylene chloride:methanol:water (4:4:1) was added 0.18 g of p-toluenesulfonic acid monohydrate, and the resulting mixture was agitated ar room temperature for 2 hours. The mixture was poured into 120 ml of water, and extracted with ethyl acetate. Distillation off of ethyl acetate afforded 2.770 g of 4,2',4'-trihydroxychalcone, having purity of 69.1% and yield of 99.9%.
Reaction SMILES: Cl.CNOC.C[Al](C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH:23]2[CH2:25][CH:19]([CH2:20][CH:21]([C:26]([O-])=[O:27])[CH2:22]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[Li:34].[O:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1.[Li]CCCC>C1COCC1>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[Li:34].[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:26]([CH:21]1[CH2:20][CH:19]2[CH2:25][CH:23]([CH2:24][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:18]2)[CH2:22]1)=[O:27]
Reactant: c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CC(C(=O)[O-])C2)C1
Agent: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CC(C(=O)c3ccco3)C2)C1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (0.068 g 0.70 mmol) in anhydrous THF (3 mL) was added trimethylaluminum (2.0 M solution in toluene, 0.35 mL, 0.70 mmol) at −10° C. After stirring for 10 min at −10° C., a solution of methyl (3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylate (0.100 g, 0.353 mmol) in THF (1 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction was then cooled to −70° C. and was treated with a freshly prepared 2-furanyllithium in THF (5 mL) solution (Note: the 2-furanyllithium was prepared by treating furan (0.24 g, 3.5 mmol) with n-BuLi (2.5 M solution in THF, 1.4 mL, 3.5 mmol) at −78° C.). The reaction mixture was warmed to ambient temperature over 1 h and quenched with saturated aqueous ammonium chloride solution (5 mL). The volatiles were removed in vacuo, and the residue was triturated with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by HPLC, to yield 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]non-7-yl)methanone (0.018 g, 16% yield). A portion of this material (4.5 mg, 14 μmol) was dissolved in a 1:1 mixture of anhydrous dichloromethane and TFA. After stirring for 1 h at ambient temperature, the volatiles were evaporated, and the resulting residue was dried on high vacuum to yield 3.2 mg (68% yield) of 2-furanyl(3-azabicyclo[3.3.1]non-7-yl)methanone trifluoroacetate as a pale yellow oil (1H NMR (CD3OD): δ 7.68 (s, 1H), 6.75 (d, J=2.68 Hz, 1H), 6.58 (m, 1H), 4.16-4.11 (m, 1H), 3.52-3.14 (m 3H), 2.64-2.57 (m 1H), 2.25-1.87 (m, 8H) (LC/MS (MH+): 220).
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[Cl:33]CCl>>[Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:33])=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: Oc1ccc(C#CCBr)cc1
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C#CCBr)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of 4-(3-bromo-prop-1-ynyl)-phenol (5.0 g, 30.12 mmol) dissolved in dichloromethane, 8.3 g (31.63 mmol, 1.05 eq) of triphenylphosphine was added and the solution was cooled to 0° C. Bromine (1.55 mL, 30.12 mmol, 1.0 eq) was added dropwise and the reaction was warmed to room temperature. The reaction was then diluted with dichloromethane, washed with sodium hydrosulfite pentahydrate, washed with brine, dried over MgSO4 and concentrated. The residue was purified via flash chromatography using 4:1 hexane:ethyl acetate to afford 5.56 g (80%) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene as an amber oil. Electrospray Mass Spec 280.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of tert-butyl (Z)-4-(3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl)piperidine-1-carboxylate (0.0802 g, 0.207 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0302 g, 0.207 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-((Z)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0724 g, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1ncnc2[nH]ccc12
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]ccc23)CC1

Procedure:
EXAMPLE 87 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4-chloro-7H-pyrrolo[2,3-d]pyrimidine was prepared according to U. Lupke, F. Seela, Chem. Ber., 112:3832–3839(1979): MS (m+1)=366.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16](C)([CH2:18][Br:19])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](Cl)(Cl)Cl>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:18]([Br:19])([CH3:27])[CH2:16][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Br
Reaction time: 96 h

Procedure:
Methyl 6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (350 mg.) was dissolved in chloroform (10 cc), and then the mixture was allowed to stand for 4 days and purified by chromatography of silica gel to give an amorphous material (200 mg.) of methyl 7-(2-phenoxyacetamido)-3-bromo-3-methylcepham-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:20](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:20]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: CCC[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2ccc(Br)cc12
Yield: 64.9 %

Procedure:
Commercially available 5-bromoindole-3-carboxaldehyde (11.3 g, 50.4 mmol), ammonium hydrogen phosphate (47.0 g, 353 mmol), 1-nitropropane (4.49 g, 50.4 mmol), and glacial acetic acid (100 ml) were heated at a gentle reflux for 18 h. The resulting mixture was concentrated in vacuo and the residue mixed with 5 N sodium hydroxide (500 ml) and ice chips. The precipitate was collected by filtration and rinsed several times with water. The filtrate was concentrated in vacuo to afford 5-bromo-3-cyanoindole (7.23 g, 65%) as a dark solid. 1H-NMR (400 MHz, CDCl3) δ10.0 (1H, s), 8.68 (1H, br s), 8.51 (1H, s), 7.85 (1H, s), 7.43 (1H, dd, J=8.6, 1.9 Hz), 7.32 (1H, d, J=8.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=3[O:27][CH3:28])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([CH3:29])([CH3:30])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[O:27][CH3:28])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: COC(=O)c1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-methyl 4-(3-(2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydropyrimidin-4-yl)-4-fluorophenylamino)-3-methoxybenzoate (example 123, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmole) and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo, the residue was dissolved in aqueous HCl (0.5N) until pH=5 and extracted with dichloromethane. The organic phase was separated, dried over Na2SO4 and evaporated to yield a white solid. The solid material was triturated with Et2O, filtered and dried to yield the title compound as a white solid. MS (ESI): m/z=429.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:42])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.Cl>C(OCC)(=O)C.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:42])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)COc1cc(CN)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.3 %

Procedure:
A suspension of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(ethoxycarbonylmethoxy) phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg) in ethyl acetate (4 mL) was added 4N hydrogen chloride in 1,4-dioxane (2 mL). The mixture was stirred for 3 h at room temperature, and concentrated in vacuo to give 135 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].CC(C)=[O:21]>O>[OH:21][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Reactant: CC(C)=O
Solvent: O
Product: CC(C)C1(C)C(=O)NC2(O)c3ncccc3C(=O)N21

Procedure:
A solution of 2 g of 3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione in 90 ml of acetone and 10 ml of water is stirred at room temperature for about 16 hours. The solution is subsequently evaporated to dryness and the residue is crystallized from ethyl acetate/n-hexane. There is obtained 1,9b-dihydro-9b-hydroxy-3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione as colorless crystals, m.p. 151°-153° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>COCCOC.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>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[C:2]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=3)[CH2:11][CH2:12][C:13]=12
Reactant: N#Cc1ccc(C2CCc3cncn32)c(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#Cc1ccc(C2CCc3cncn32)c(-c2ccc(F)cc2)c1
Temperature: 130 °C

Procedure:
To a solution of 3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.100 g, 0.347 mmol) and 4-fluorophenylboronic acid (0.158 g, 1.04 mmol) in DME (2 mL), aqueous solutions of Na2CO3 (0.69 mL, 2 M) and KOH (0.17 mL, 2 M) are added. After degassing with nitrogen, Pd(PPh3)4 (0.040 g, 0.035 mmol) is added. Mixture is heated in a microwave reactor at 130° C., for 20 minutes. LCMS showed consumption of starting material. The solution is then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The resulting aqueous layer is extracted further with ethyl acetate (3×). The combined organic layers are washed with brine and dried over anhydrous sodium sulfate. After concentration, crude product is purified by flash chromatography (Hexane/EtOAc, and then 10% MeOH/DCM) followed by preparative HPLC (0-50% acetonitrile with 0.1% TFA in 21 minutes). After concentration and free basing, 6-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-fluorobiphenyl-3-carbonitrile is obtained as a white powder. MS (ESI) m/z 304.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.54 (m, 1 H), 2.76-3.03 (m, 3 H), 5.33 (app t, J=6.7 Hz, 1 H), 6.79 (s, 1 H), 7.01 (d, J=8.1 Hz, 1 H), 7.15-7.24 (m, 3 H), 7.29 (dd, J=13.4, 5.1 Hz, 2 H), 7.54-7.65 (m, 2 H).