Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C

Procedure:
30 g (70.7 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate in 500 ml of dioxane are introduced into a three-necked flask. The reaction medium is degassed, 30 g of palladium on carbon (10%) are added and the mixture is hydrogenated at a pressure of 3 bar at 60° C. The reaction medium is filtered, evaporated off and the residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (99–1) mixture. 18 g (60%) of the expected product are recovered after evaporation of the solvents.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH:6](=[C:10]1[S:14][C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9].[OH-].[Na+]>C(O)(=O)C>[CH:6](=[C:10]1[S:14][C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[N:26]3[C:27]([CH2:3][N:4]([CH3:1])[CH3:5])=[CH:28][N:29]=[C:25]3[CH:24]=[CH:23][CH:22]=2)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(CN(C)C)n23)C1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.27 ml (3.6 mmol) of formalin and 0.33 g (3.6 mmol) of a 50% aqueous dimethylamine solution in 20 ml of acetic acid, a solution of 1.13 g (3.0 mmol) of 5-butylidene-3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione in 5 ml of acetic acid was added at 0° C., followed by stirring at 80° C. for 90 minutes. After cooling, the reaction mixture was poured into 50 ml of 50% aqueous sodium hydroxide under ice cooling conditions. The mixture was extracted with chloroform and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 0.43 g (33.3%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH2:14]=O.Cl.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][CH2:17][N:18]([CH3:14])[CH3:19])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: CNC
Reactant: C=O
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)CCN(C)C)cc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred solution of 3,4-Dimethoxy acetophenone (3 g, 0.0166 moles, 1 equiv.) in ethanol was added paraformaldehyde (0.5 g, 0.0166 moles, 1 equiv.), dimethylamine hydrochloride (4.2 g, 0.0499 moles, 3 equiv.) and the reaction mixture was refluxed at 80° C. for 12 h. Consumption of starting materials was confirmed by LC-MS analysis and TLC. Ethanol was evaporated under reduced pressure; the crude solid residue was stirred with acetone at 0° C. for 1 h, filtered, washed with acetone, dried under vacuum. After that the solid was suspended in water, basified with 10% sodium bicarbonate solution (pH˜8), extracted by dichloromethane (2×200 ml), washed with water followed by satd. Brine solution. The organic layer was dried over sodium sulfate and concentrated to get 2.9 g (73% yield) title compound as green oily liquid. It was taken forward for the next step without any further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Br[CH:6]([C:12]([O:14][CH2:15]C)=[O:13])[C:7]([O:9][CH2:10]C)=[O:8].[CH3:17][OH:18]>C(OCC)C>[CH3:1][O:2][C:6]([O:18][CH3:17])([C:12]([O:14][CH3:15])=[O:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)C(OC)(OC)C(=O)OC

Procedure:
To a solution of sodium methoxide prepared by dissolving 5.75 grams (0.25 mole) of sodium in 375 milliliters of anhydrous methanol was added 59.8 grams (0.25 mole) of diethyl bromomalonate in one portion and the resulting mixture heated under reflux for 4 hours. The mixture was freed of methanol solvent under reduced pressure and the residue taken up in ethyl ether and filtered to remove by-product solids. The filtrate was freed of ether under reduced pressure and the residue vacuum distilled In a short-path system to give 6.49 grams (0.03 mole) of dimethyl dimethoxymalonate boiling over a range of 100° C.-125° C. at 1.4-1.8 Mm of Hg. NMR analysis of the product indicated the following:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[CH2:35]([CH:42]1[CH2:47][CH2:46][N:45]([C:48]2[C:53]([Br:54])=[CH:52][N:51]=[C:50]([NH2:55])[C:49]=2[N+:56]([O-])=O)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[CH2:35]([CH:42]1[CH2:47][CH2:46][N:45]([C:48]2[C:53]([Br:54])=[CH:52][N:51]=[C:50]3[NH:55][C:67]([C:69]4[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=4)=[N:56][C:49]=23)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ncc(Br)c(N2CCC(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Cc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 22.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 4-(4-benzylpiperidin-1-yl)-5-bromo-3-nitropyridin-2-amine (100 mg, 0.25 mmol), DMF (0.20 mL), ethanol (1.25 mL), 1M Na2S2O4 (3 eq, 0.75 mmol, 0.75 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.28 mmol, 66 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (32 mg, 22%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 1.44-1.49 (m, 2H, 2× piperidine CHAHB), 1.73 (app d, J=11.0 Hz, 2H, 2× piperidine CHAHB), 1.78-1.85 (m, 1H, piperidine CH), 2.61 (app d, J=7.1 Hz, 2H, PhCH2), 3.31-3.34 (m, 2H, 2× piperidine NCHAHA), 3.85 (app d, J=11.9 Hz, 2H, 2× piperidine NCHAHA), 4.19 (d, J=7.9 Hz, 2H, CH2—NHBOC), 7.20 (t, J=7.3 Hz, 1H, phenyl H-4), 7.23 (d, J=7.0 Hz, 2H, phenyl H-2 & H-6), 7.31 (t, br, J=7.4 Hz, 2H, phenyl H-3 & H-5), 7.38 (d, J=8.2 Hz, 2H, phenyl H-3′ & H-5′), 7.43 (t, br, J=5.9 Hz, 1H, CH2—NHBOC), 8.11 (d, J=8.9 Hz, 2H, phenyl H-2′ & H-6′), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.03 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.C[O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=1Br.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:14]4[CH:15]=[C:10]([CH:11]=[C:12]([N:3]5[CH2:2][CH2:1][NH:6][C:4]5=[O:5])[CH:13]=4)[C:9]([OH:8])=[O:18])[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: O=C1NCCN1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(I)ccc1Br
Product: O=C(O)c1cc(N2CCNC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 92 starting from ethyleneurea (commercially available), bromo-5-iodo-benzoic acid methyl ester prepared as in Example 92, (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C26H20ClN3O4: 473, observed (M+H)+: 474.21H NMR (400 MHz, DMSO-d6) δppm 2.14 (dd, J=9.22, 4.93 Hz, 1 H) 2.41 (dd, J=7.96, 4.67 Hz, 1 H) 3.22-3.28 (m, 1 H) 3.43-3.49 (m, 1 H) 3.92-3.98 (m, 1 H) 6.19 (d, J=7.58 Hz, 1 H) 6.80 (t, J=7.71 Hz, 1 H) 6.85 (d, J=7.83 Hz, 1 H) 7.12 (t, J=8.34 Hz, 1 H) 7.22 (s, 1 H) 7.42 (q, J=8.59 Hz, 3 H) 7.64 (s, 1 H) 7.99 (t, J=2.02 Hz, 1 H) 8.13 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CO>CCOC(C)=O.[Pd]>[CH:29]1([CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(/C=C/C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCC(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [rac]-4-{(E)-3-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3-cyclohexyl-propenyl}-benzoic acid (0.227 mmol; example 67.3) in 3 ml EtOAc was added 30 mg Pd (5%) on charcoal. 3 ml MeOH was added. The reaction mixture was vigorously stirred at room temperature under 1.5 bar H2 pressure for 1 hours. The reaction mixture was filtrated over dicalite and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>C(O)C>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(N)s1
Solvent: CCO
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 132.5 %

Procedure:
To 10 ml of ethanol, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 3 hours. After the reaction mixture was cooled, crystals so precipitated were collected by filtration, washed successively with ethanol and diethyl ether and then dried, whereby 2.54 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(C(F)(F)F)cc5)cccn4n3)cc2)CC1

Procedure:
8-(4-Trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (504.7 mg, 2.369 mmol) and (4-trifluoromethylphenyl)boronic acid (500.0 mg, 2.632 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a yellow solid (0.64 g, 97%). MP=186-187° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.62 (d, J=6.3 Hz, 1H), 8.34 (d, J=8.0 Hz, 2H), 7.88-7.80 (m, 3H), 7.02 (t, J=6.8 Hz, 1H), 6.18 (s, 2H). MS=279 (MH)+. 64b) [4-(4-Methyl-piperazin-1-yl)-phenyl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.270 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.033 g, 27%). MP=214-216° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44 (d, J=6.5 Hz, 1H), 8.12 (dm J=8.7 Hz, 2H), 7.77 (d, J=7.4 Hz, 2H), 7.59 (d, J=7.4 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.00-6.93 (m, 3H), 6.66 (s, 1H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=453 (MH)+.
Reaction SMILES: C[O-].[Na+].[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][C:26](=O)[CH3:27])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCC[CH2:33][OH:34].O>CO>[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][CH2:26][CH2:27][CH2:33][OH:34])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: OCCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CSCCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
5 ml of a methanolic solution containing 0.26 g of a 28% w/v sodium methoxide solution were added, whilst ice-cooling, to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(acetylthio)acetamide [prepared as described in step (b) above] in 5 ml of methanol, and the resulting solution was stirred for 20 minutes. At the end of this time, a solution of 0.11 ml of 3-chloro-1-propanol in 5 ml of methanol, was added, and the reaction mixture was heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.42 g (yield 81%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Br)c(S)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Br)c(SC)c1
Reaction time: 2 h

Procedure:
The product of step (c) above (140 mg) was dissolved in dry dimethyl formamide (2 ml). Potassium carbonate (114 mg) was added followed by methyl iodide (47 ml). The mixture was stirred for 2 hours, poured onto water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine then dried and evaporated to leave the subtitle compound as a pale brown oil MS MW 232/4 bp 232.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH2:15][C@@H:16]([OH:19])[CH2:17][OH:18])[C:5]2=[O:20].CC(O)=O.[H][H].[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([O:36][CH3:37])[N:31]=[CH:30][CH:29]=1>CO.[Pd]>[Cl:27][C:28]1[CH:29]=[CH:30][N:31]=[C:32]([O:36][CH3:37])[C:33]=1[C:34]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:14])[N:6]([CH2:15][C@@H:16]([OH:19])[CH2:17][OH:18])[C:5](=[O:20])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: [H][H]
Reactant: COc1nccc(Cl)c1C=O
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(C[C@@H](O)CO)C2=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C[C@@H](O)CO)C3=O
Temperature: -30 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
To a suspension of (R)-5-amino-2-(2,3-dihydroxypropyl)-6-nitroisoindoline-1,3-dione (0.50 g, 1.78 mmol) in 100 mL of MeOH was added 5 mL of AcOH. The resulting solution was degassed with Argon and then charged with 10% Pd/C (0.19 g, 50% wet, 0.089 mmol) and hydrogenated at 40 psi of hydrogen for 16 h. Another 5 mL of AcOH was added to the mixture and then solids were filtered off. The filtrate was cooled to −30° C. and a solution of 4-chloro-2-methoxynicotinaldehyde (0.31 g, 1.78 mmol) in 50 mL of MeOH was added dropwise under inert atmosphere. The resulting red clear solution was allowed to warm up to rt and stirred for 16 h. Solvent was evaporated and the oily residue was purified by column chromatography (7.5% MeOH in dichloromethane) to give title compound as a yellow solid (0.21 g, 29.3%). 1H NMR (500 MHz, DMSO-d6) δ58.37 (d, J=5.5 Hz, 1H), 8.07 (s, 2H), 7.40 (d, J=5.5 Hz, 1H), 4.92 (d, J=5.0 Hz, 1H), 4.67 (br s, 1H), 4.20-4.14 (br s, 1H), 3.90 (s, 3H), 3.90-3.80 (m, 1H), 3.64-3.60 (m, 2H), 3.42-3.36 (m, 2H). ESI MS: m/z 403.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.BrC(C)C(=O)C=CC1C=CC(C#N)=CC=1.NC1C=C(C(OC)=O)C=CN=1.[CH2:50]([O:52][C:53]([CH2:55][CH2:56][NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:54])[CH3:51].C(OCC)(=O)C.C(O)C.N>S(Cl)(Cl)=O>[C:58]1([N:57]([CH2:56][CH2:55][C:53]([O:52][CH2:50][CH3:51])=[O:54])[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([CH3:1])=[C:3]([CH2:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=4)[N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Cc1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)ccn12
Reactant: CCOC(=O)CCNc1ccccc1
Agent: CC(Br)C(=O)C=Cc1ccc(C#N)cc1
Agent: COC(=O)c1ccnc(N)c1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reaction time: 1 h

Procedure:
1.4 g (4.6 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic acid (prepared from 4-bromo-1-(4-cyanophenyl)-1-penten-3-one and methyl 2-aminopyridine-4-carboxylate analogously to Y. Katsura et al. Chem. Pharm. Bull. 1992, 40, 1424-1438) were suspended in 15 ml of thionyl chloride and heated to boiling for 1 hour until fully dissolved. After the thionyl chloride had been distilled off the acid chloride was dissolved in 15 ml of pyridine without any further purification and at 0° C. mixed with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)-aniline. After 1 hour the solvent was distilled off, the residue was taken up in 30 ml of methylene chloride, washed with 15 ml of 1N hydrochloric acid and dried with sodium sulphate. After distillation of the solvent and chromatography (silica gel; methylene chloride/ethanol=0 to 2%) a brown oil was obtained. Yield: 1.48 g (64% of theory), Rf value: 0.73 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1)
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Br.[Br:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)NCCCBr
Reaction time: 1 h

Procedure:
Diketene (1.22 mL, 15.7 mmol, 1.50 equiv) was added at room temperature to a stirred mixture of 3-bromopropylamine hydrobromide (2.30 g, 10.5 mmol, 1.00 equiv) and triethylamine (1.46 mL, 10.5 mmol, 1.00 equiv) in anhydrous THF (20 mL) under argon, and stirring was continued at room temperature for 1 hour. The solvent was removed and the residue was purified by flash chromatography (SiO2, MeOH--CH2Cl2 0:1 to 1:18) to afford a light yellow oil, 2.10 g (90%), which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH3:1].[N:9]1[NH:10][N:11]=[N:12][C:8]=1[C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccnc1N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N
Product: Nc1ncccc1-c1nn[nH]n1
Yield: 97 %

Procedure:
2-Amino-3-cyanopyridine (1.0 g), sodium azide (1.1 g), ammonium chloride (0.89 g), and DMF (15 mL) were stirred for 1.5 hours at 100° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:0.5) to obtain the titled compound (0.66 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:32])[C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)#[N:12].ClCCl.[CH3:36][OH:37]>N1C=CC=CC=1>[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:17](=[O:22])[C:16]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[O:32][C:36]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:37])#[N:12]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(C#N)cc21
Reaction time: 2 h
Yield: 87 %

Procedure:
4.63 ml (36.98 mmol) of phenyl chloroformate were slowly added dropwise, undiluted, at the preset temperature to a suspension, cooled to 0° C., of 5.20 g (17.61 mmol) of (±)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one from example 1.2 in 100 ml of pyridine. After the reaction mixture had thawed to room temperature it was stirred for 2 hours. The progress of the reaction was followed by thin-layer chromatography (silica gel, dichloromethane/methanol 9:1). Excess pyridine was removed in vacuo, and the residue was poured into 200 ml of ice-water and extracted with ethyl acetate (3×). The organic phase was washed with water (2×). Traces of pyridine were still present in the phase. The organic phase was dried over sodium sulfate. After removal of the ethyl acetate in vacuo, the remaining pyridine was driven off by addition of toluene and removal in vacuo several times. The residue was dried under high vacuum. 8.20 g (15.31 mmol, 87%) of phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)-oxy]indoline-1-carboxylate were obtained.