Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]2[N:6]([C:8]([C:12]([NH:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C(OCC)(=O)C.[CH3:38][N:39]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:38]([C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]2[N:6]([C:8]([C:12]([NH:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1)#[N:39]
Reactant: CN1CCCC1=O
Reactant: Cc1nc2c(OCC3CCCCC3)cc(Br)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cc(C#N)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
To a solution of 90 mg of 6-bromo-8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 1.8 ml of N-methyl-2-pyrrolidone were added 54 mg of zinc cyanide and 27 mg of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II), followed by stirring at 180° C. for 30 minutes under a condition for microwave irradiation. To the reaction mixture was added 46 mg of zinc cyanide, followed by further stirring at 180° C. for 30 minutes under a condition for microwave irradiation. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by filtration through Celite. A layer separation operation of the obtained filtrate was carried out, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7 mg of 6-cyano-8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([C:6]1[C:10]([C:11](OCC)=[O:12])=[CH:9][N:8]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[N:7]=1)=O.[CH3:28][NH:29][NH2:30]>C(O)C>[CH3:28][N:29]1[C:11](=[O:12])[C:10]2=[CH:9][N:8]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[N:7]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:27])[CH3:1])=[N:30]1
Reactant: CCOC(=O)c1cn(Cc2cccc3ccccc23)nc1C(=O)CC(C)C
Reactant: CNN
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3cccc4ccccc34)nc12

Procedure:
Ethyl 3-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-4-carboxylate (1.8 g) and methylhydrazine (0.6 ml) in ethanol (20 ml) were heated underreflux for 16 hours. The solution was cooled and evaporated to a solid, which was purified by chromatography on silica (ethyl acetate:isohexane 2:3) followed by crystallisation from ethyl acetate/cyclohexane to give 2,5-dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4H-pyrazolo[3,4-d]pyridazin-4-one (0.43 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)C([Cl:16])=O>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-difluorophenylacetic acid (10.24 g, 60.4 mmol) in tetrahydrofuran (200 mL) and dimethylformamide (5 drops) at room temperature was added in 1 mL portions oxalyl chloride (11 mL, 126 mmol). The reaction mixture was stirred 2 hours at room temperature and concentrated to an orange liquid that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-])=O.[Sn](Cl)Cl.C(OC)(C)(C)C.[Cl-].[Na+]>Cl.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[NH2:7]
Reactant: Cc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: Cc1nc(-c2cccnc2)sc1N
Reaction time: 1 h

Procedure:
10.1 g (45.6 mmol) of 3-(4-methyl-5-nitro-1,3-thiazol-2-yl)pyridine (for preparation see DE 2221647) were dissolved in 100 ml of 10% hydrochloric acid together with 10 ml of conc. hydrochloric acid, and 25 g of tin(II) chloride dissolved in 10% hydrochloric acid were added in portions, and the mixture was stirred for 1 h (hour), in the course of which heating occurred. The mixture was poured into ice/sodium hydroxide solution, methyl t-butyl ether, ethyl acetate and saturated sodium chloride solution were added, the mixture was extracted 4 times at pH=10 with ethyl acetate, the combined organic phases were dried with MgSO4 and the mixture was concentrated. The residue was recrystallized from benzotrifluoride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([NH:25][CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20].N1C=CC=CC=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>O1CCCC1>[Cl:3][C:4]1[CH:24]=[C:23]([N:25]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: CNc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate dihydrochloride (418 mg), pyridine (396 mg) and tetrahydrofuran (4.2 ml) was added dropwise ethyl chlorocarbonate (0.115 ml) under ice-cooling and the mixture was stirred at room temperature for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was pulverized in diethyl ether to give methyl 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (340 mg) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].Cl>O.CO>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 65 °C
Yield: 80.5 %

Procedure:
To a solution of ethyl-3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylate (500 mg, 1.2 mmol) in a solution of tetrahydrofuran, methanol, and water (2:1:1) (4 mL) was added sodium hydroxide (200 mg, 5 mmol). The reaction was allowed to reflux overnight at 65° C. The solution was neutralized with 1 N HCl and extracted with ethyl acetate to yield the title compound (350 mg, 40% yield). ES-MS (m/z) 363 [M+1]+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][CH2:12][CH:11]2[CH:7]([C:8](=O)[C:9](=[O:14])[NH:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H][H].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd].[Rh]>[CH2:1]([CH:5]1[CH2:13][CH2:12][CH:11]2[CH:7]([CH2:8][C:9](=[O:14])[NH:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCC1CCC2NC(=O)C(=O)C2C1
Agent: [Pd]
Agent: [Rh]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCCC1CCC2NC(=O)CC2C1

Procedure:
For example, a solution of 5-n-butyl-octahydro-2,3-dioxo-1H-indole (III) (43.6 g, 0.214 mole) in acetic acid (250 ml) is treated with hydrogen gas in the presence of 20% Pd/C (2 g). Another 1 g of 20% Pd/C is added and concentrated sulfuric acid (1 ml) is added and the hydrogenation is continued. Ten percent Rh/C (2 g) is added and hydrogenation is continued. The suspension is filtered and sodium acetate (4.9 g, 0.06 mole) is added and the mixture is concentrated at reduced pressure The residue is recrystallized from cyclohexane with the use of activated carbon to yield pure 5-n-butyloctahydro-2-oxo-1H-indole (V) with a mp 109°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1F)[C:5]([N:7]1[CH2:10][CH2:9][CH2:8]1)=[O:6].[OH:15][C:16]1[CH:17]=[C:18]([CH:34]=[C:35]([O:37][C@@H:38]([CH3:51])[CH2:39][O:40][Si](C(C)C)(C(C)C)C(C)C)[CH:36]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24](C(OC(C)(C)C)=O)[N:23]=1)=[O:20]>>[N:7]1([C:5]([C:4]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:17]=[C:18]([CH:34]=[C:35]([O:37][C@@H:38]([CH3:51])[CH2:39][OH:40])[CH:36]=3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][NH:24][N:23]=3)=[O:20])=[C:2]([F:1])[CH:3]=2)=[O:6])[CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2cc[nH]n2)c1

Procedure:
The synthesis of 1-(3,4-difluorobenzoyl)azetidine is described in Example 8, the synthesis of tert-butyl 3-[(3-hydroxy-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoyl)amino]-1H-pyrazole-1-carboxylate is described below:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[C:14]([F:20])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][C:23]=1[C:29](=[O:31])[CH3:30]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15](/[CH:16]=[CH:17]/[C:27]3[C:22]([OH:21])=[C:23]([C:29](=[O:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[C:14]([F:20])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(I)c1O
Reactant: C=Cc1ccc(OCCCCc2ccccc2)cc1F
Product: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2F)c1O
Yield: 67 %

Procedure:
Following the process described in example 20 (point D), starting from 4-(4-phenylbutoxy)-2-fluorostyrene and 2'-hydroxy-3'-iodoacetophenone, the title compound was prepared, which was purified by flash chromatography through a column, eluting with petroleum ether:ethyl acetate, 95:5 (67% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:4][C:3]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=2[CH3:1])[CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Temperature: 110 °C
Yield: 78.6 %

Procedure:
2.64 g of 2-methyl-5-nitroaniline and 10.33 g of 4,6-dichloropyrimidine were stirred with heating at 110° C. for 16 hours. After air cooling, the reaction solution was dissolved in methanol. An aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added to separate the aqueous layer. The aqueous layer was further subjected to extraction with ethyl acetate twice. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was washed with diisopropyl ether to obtain 3.61 g of the objective compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:28][CH:27]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 5-bromo-2-oxindole (42 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([C:22]([F:32])([F:21])[F:31])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: OC1CCC(N2CCc3[nH]c4ccc(Cl)cc4c3C2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OC1CCC(N2CCc3c(c4cc(Cl)ccc4n3CCc3ccc(C(F)(F)F)nc3)C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(8-chloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol (300 mg, 1.03 mmol), 2-trifluoromethyl-5-vinylpyridine (140 mg, 0.809 mmol) and potassium hydroxide (310 mg, 5.5 mmol) in 0.6 ml of NMP was heated to 60 deg C. for 2 h. The reaction mass was cooled at RT and diluted with 20 ml of ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate and concentrated under vacuum. It was purified on 230-400 silica gel (flash) deactivated with triethylamine using ethyl acetate/methanol (5-10%) as eluant, followed by isolation of 3-(8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol by PREP HPLC. Yield: 70 mg as TFA salt.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:44]([C:46]1[N:47]=[CH:48][N:49]2[C:54](=[O:55])[N:53]([CH2:56][C:57]#[CH:58])[N:52]=[N:51][C:50]=12)=O>C(Cl)Cl>[NH:43]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:44]1[C:46]1[N:47]=[CH:48][N:49]2[C:54](=[O:55])[N:53]([CH2:56][C:57]#[CH:58])[N:52]=[N:51][C:50]=12
Reactant: C#CCn1nnc2c(C(=O)Nc3ccccc3N)ncn2c1=O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C#CCn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46.6 %

Procedure:
Triflic anhydride (82 μL, 0.485 mmol) was added dropwise at 0° C. under nitrogen to a solution of triphenylphosphine oxide (135 mg, 0.485 mmol) in DCM (1.5 mL) and the mixture was stirred at 0° C. for 20 minutes. The resulting solution was then added dropwise at 0° C. under nitrogen to a stirred suspension of N-(2-aminophenyl)-4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (50 mg, 0.162 mmol) in DCM (1.5 mL). The resulting dark brown mixture was stirred for 3 days and the precipitate, which formed during the reaction, was filtered. The solid was dissolved in MeCN:MeOH and triethylamine (75 μL) was added. The mixture was stirred for about 5 minutes and was then concentrated under vacuum. The crude product was suspended in ethyl acetate and the resulting suspension was filtered. The solid was washed with ethyl acetate to give the pure title compound as a bright yellow solid (22 mg, 47%). (Less triethylamine (100 μL/250 mg starting material) was used during the neutralization on larger scale preparations.) δH (DMSO d6): 13.1 (1H, s), 9.02 (1H, s), 7.73-7.75 (1H, m), 7.56-7.58 (1H, m), 7.22-7.27 (2H, m), 5.15 (2H, d, J=2.5), 3.53 (1H, t, J=2.5).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27](Cl)=[O:28])=[CH:20]2)[CH3:16]>C(Cl)Cl>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:28])=[CH:20]2)[CH3:16]
Reactant: COC(=O)CN
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc2nnc(C(=O)NCC(=O)OC)cc2c1
Reaction time: 5 h

Procedure:
A mixture of glycine methyl ester hydrochloride (2.5 g.) and triethylamine (2.6 ml.) in dry methylene chloride (10 ml.) was added to a solution of 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.) in dry methylene chloride (10 ml.). The resulting solution was kept at room temperature for 5 hours, diluted with methylene chloride (80 ml.) and washed successively with N-hydrochloric acid, water, 10% w/v sodium bicarbonate solution, and water and then dried (MgSO4). The solvent was evaporated and the solid residue was crystallized from aqueous ethanol to give 6-ethyl-N-(methoxycarbonylmethyl)-cinnolin-3-yl carboxamide, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:4][C:3]=1Cl.C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20]2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3ccnc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 1, METHOD A, Step 5, 70 mg, 0.19 mmol), ammonium formate (120 mg, 1.9 mmol) and 10% palladium on carbon (50 mg) in methanol (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was filtered through a pad of Celite, and the filtrate was basified with 25% aqueous ammonia. This was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (90:10:1) to give 40 mg (63%) of the title compound as a gum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[CH:23](OCC)(OCC)OCC>>[Br:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:23][N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2N)C1
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)N1CCCC(n2cnc3cnc(Br)cc32)C1
Yield: 69.9 %

Procedure:
A mixture of tert-butyl 3-((5-amino-2-bromopyridin-4-yl)amino)piperidine-1-carboxylate (1.1 g, 3.0 mmol, 1.0 eq) in CH(OCH2CH3)3 (214 mg, 30 mmol, 10 eq) was refluxed for 40 h. Then the residual CH(OCH2CH3)3 was removed in vacuum and the crude product was purified by silica gel column chromatography with EtOAc in PE (½ v/v) to give the title compound (0.8 g, 70%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ: 8.87 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 4.30-4.28 (m, 2H), 4.02-4.00 (m, 1H), 3.27-3.22 (m, 1H), 3.09-3.03 (m, 1H), 2.31-2.30 (m, 1H), 2.13-2.10 (m, 1H), 1.88-1.85 (m, 1H), 1.74-1.71 (m, 1H), 1.50 (s, 9H). ESI-MS (M+H+): 381.0.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reaction time: 24 h
Yield: 96 %

Procedure:
A solution of methyl 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 30)(5.23 g, 11.93 mmol) in MeOH (80 mL) was treated with aqueous lithium hydroxide (1M, 17.89 mL, 17.89 mmol) and the resulting mixture, which became a suspension after 5 min was stirred. After 24 h, lithium hydroxide (17.89 mL, 17.89 mmol) was added and the mixture (which by then was a solution) was stirred at 50° C. for 3 h. The mixture was cooled to room temperature, most of the MeOH was evaporated in vacuo and the residue treated with acetic acid (2.73 mL, 47.7 mmol). After 5 min, a precipitate formed, was isolated by filtration, washed with water and dried at 45° C. under vacuum for 16 h to give 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (4.88 g, 11.50 mmol, 96% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.70 min, MH+=425.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[OH-].[K+].[CH3:15]I>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[Cl:11])[N:4]([CH3:15])[N:3]=1
Reactant: CI
Reactant: Nc1nc(Cl)c2c(Br)n[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(Br)c2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (580 mg, 2.3 mmol) is dissolved in DMF (40 ml), potassium hydroxide (131 mg, 2.3 mmol) is added and the reaction mixture is stirred at room temperature for 15 minutes. Methyl iodide (0.133 ml, 2.3 mmol) is then added and the reaction is continued stirring overnight. The reaction mixture is diluted with water (60 ml) and EtOAc (60 ml), the layers are separated and the organic portion is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:5]([CH:8]([CH3:10])[CH3:9])([CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]#[N:7])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CNCCc1ccccc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2)C(C)C)cc1OC

Procedure:
Reaction of 1f with N-methyl-2-phenylethanamine produced 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile which was further reacted in a manner analogous to the procedure reported in Liang, C. D. et al., Tetrahedron Lett., (1986) 27, 1971-1974.
Reaction SMILES: [C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3]I.[C:16]([OH:23])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1.C([O-])(=O)CCCCC.[Ag+]>[C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3][O:23][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(OCI)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCC(=O)O
Agent: [Ag+]
Agent: CCCCCC(=O)[O-]
Solvent: c1ccccc1
Product: CCCCCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 116.2 %

Procedure:
A solution of 0.25 g of iodomethyl p-nitrophenyl carbonate and 0.5 g hexanoic acid was heated to reflux in benzene with 0.5 g of silver hexanoate. After two hours the reaction mixture was filtered, and the filtrate was washed successively with aqueous sodium bicarbonate and water. After drying over sodium sulfate, the solvent was evaporated to furnish hexanoyloxymethyl p-nitrophenyl carbonate as a light yellow liquid (0.28 g). IR (film) 1775 (C=O). NMR (CDCl3) 0.9 (t, 3H, J=7 Hz, Me), 1.1-2.0 (m, 6H, (CH2)3), 2.41 (t, 2H, J=7 Hz, COCH2), 5.88 (s, 2H, OCH2O), 7.38 (d, 2H, J=10 Hz, aromatic), 8.21 (d, J=10 Hz, 2H, aromatic).