Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[NH:15][C:16]([C:18]3[C:19](=[O:34])[NH:20][CH:21]=[CH:22][C:23]=3[NH:24][CH2:25][C@@H:26]([OH:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N>C1COCC1>[OH:33][C@@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:23]1[CH:22]=[CH:21][NH:20][C:19](=[O:34])[C:18]=1[C:16]1[NH:15][C:14]2[C:9]([NH:8][C:42](=[O:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Reactant: O=C(Cl)Cc1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Triethylamine (0.058 g, 0.416 mmol) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and phenylacetyl chloride (0.051 g 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours methanolic ammonia was added (5 ml) and the reaction stirred for a further 20 hours. The reaction mixture was concentrated under reduced pressure and the crude solid washed with acetonitrile water (1:1; 10 ml) to give the desired product (0.034 g; 43%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[N:17]([CH3:18])[C:16](=[O:19])[C:15]([OH:20])=[C:14]2[CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:13]2=[O:21])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[CH2:11][CH2:10][CH:9]3[C:14](=[C:15]([OH:20])[C:16](=[O:19])[N:17]([CH3:18])[CH:8]3[C:6]([OH:7])=[O:5])[C:13]2=[O:21])=[CH:24][CH:25]=1
Reactant: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)O
Reaction time: 1.3 h

Procedure:
A solution of 5-(tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, Diastereomer 1 from Example 4, (0.015 g, 0.037 mmol) in 50% TFA in CH2Cl2 (2.4 mL) was stirred at room temperature. After 1.3 hours, TFA acid (0.5 mL) was added to the reaction mixture. After 48 hours, the reaction mixture was concentrated under vacuum to give the title compound. ES MS M+1=349.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: CCCCBr
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cc(C=O)cc(OC)c1OCCCC
Yield: 98.8 %

Procedure:
A mixture 3-allyl-4-hydroxy-5-methoxybenzaldehyde (10.25 g, 0.053 mole), of dimethylformamide (150 ml), of potassium carbonate (8.29 g, 0.06 mole) and of 1-bromobutane (8.22 g, 0.06 mole) was maintained at 40°-45° C. for 3 hours. The reaction mixture was dropped into iced water and the oil formed was extracted with dichloromethane. After washing with water, drying and evaporating off the solvent, a brown oil was obtained, which was passed through a bed of silica 60 to give a pale yellow oil of 3-allyl-4-butoxy-5-methoxybenzaldehyde (13 g, yield=91%).
Reaction SMILES: [C:1]([C@H:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5])(=[S:3])[NH2:2].[CH2:41](OC(OCC)CBr)[CH3:42].Cl>CC(C)=O.O1CCOCC1>[S:3]1[CH:42]=[CH:41][N:2]=[C:1]1[CH:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]#[N:40])=[CH:37][CH:38]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5]
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=S
Reactant: CCOC(CBr)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(NC(=O)[C@H](C)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)c1nccs1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [(S)-1-((R)-1-thiocarbamoyl-ethylcarbamoyl)-ethyl]-amide (132 mg, 0.22 mmol) in 1 mL of acetone was added bromoacetaldehyde diethyl acetal (0.166 mL, 1.10 mmol) and HCl in dioxane (4 M, 0.003 mL, 0.01 mmol). The reaction mixture was heated at reflux for 5 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to a pale brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-5% MeOH in CH2Cl2, to furnish 122 mg (89%) of the title compound as a pale brown foam, obtained as a 1:1 mixture of thiazole α-methyl diastereomers, m/z 622.3 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:66])[NH:26][C:27]([C:29]1[S:30][C:31]([S:64][CH3:65])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=3[NH:51][C:52]([NH:54][CH2:55][CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:53])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)=[NH:28])([CH3:23])([CH3:22])[CH3:21]>CO.C(O)(=O)C>[C:20]([O:24][C:25](=[O:66])[NH:26][C:27]([C:29]1[S:30][C:31]([S:64][CH3:65])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([NH:50][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:45][C:44]=3[NH:51][C:52]([NH:54][CH2:55][CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:53])[CH:40]=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH:33]=1)=[NH:28])([CH3:22])([CH3:23])[CH3:21]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCNc2ccccc2)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
1,3-Bis-t-butoxycarbonyl-2-methyl-2-thiopseudourea (0.033 g, 0.114 mmol) was added to a solution of [(4-{4′-amino-6′-methyl-2′-[3-(2-phenylamino-ethyl)-ureido]-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester [example 216, step a] in methanol [1 mL] and 1 drop of acetic acid. The reaction was stirred at room temperature for 1 hour and evaporated. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.072 g, 68%) as a solid. ESI-MS (m/z): Calcd. for C44H56N8O9S3: 936.33; found: 936.9.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([C:21]#[C:22][CH2:23][OH:24])[CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C#C>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([CH2:21][CH2:22][CH2:23][OH:24])[CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C#CCO)ccc2c1O
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(CCCO)ccc2c1O
Yield: 47.6 %

Procedure:
A mixture of the title compound of Example 101 (0.190g) and Pd/C (10%, 37.9 mg) is dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 25 psi H2 and monitored with the OAMS for complete reduction of the acetylene. The reaction is filtered and fresh catalyst is added each time the reaction is taken off the Parr. The reaction is completed in 31/2 hrs and filtered over celite to remove the palladium. The filtrate is condensed to obtain a residue. The residue is dissolved in MeOH, adsorbed onto silica, and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to yield 91.4 mg of the desired product as a white solid.
Reaction SMILES: CC1(C)O[CH:5]([N:7](C)[C:8](=[O:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])[CH2:4][O:3]1.FC(F)(F)[C:24](O)=[O:25]>ClCCl>[OH:3][CH:4]([CH2:24][OH:25])[CH2:5][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=[O:18])[CH3:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1ccccc1C(=O)N(C)C1COC(C)(C)O1
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)NCC(O)CO
Reaction time: 0.5 h

Procedure:
The solution from 2-acetoxybenzoic acid 2,2-dimethyl-[1,3]dioxolan-4-yl-methylamide (184 mg, 0.63 mmol) in dichloromethane (5 ml) is treated with trifluoroacetic acid (1 ml). After 0.5 h at room temperature, the mixture is concentrated, the residue is taken up in toluene (10 ml) and the solution is concentrated. The residue is purified by column chromatography (dichloromethane/methanol=10/1). Yield: 132 mg.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:19]4[C:20]5[CH:28]=[CH:27][CH:26]=[N:25][C:21]=5[N:22]=[CH:23][N:24]=4)C(=O)NC(=O)NC3=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:19]3[C:20]4[CH:28]=[CH:27][CH:26]=[N:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=O)C(c2ccc3c(c2)CCC3)(c2ncnc3ncccc23)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cnc2ncnc(Cc3ccc4c(c3)CCC4)c2c1
Yield: 60 %

Procedure:
A solution of 5-(5-indanyl)-5-(pyrido[2,3-d]pyrimidin-4-yl) barbituric acid (3.734 g, 10 mM) and sodium hydroxide (2.00 g, 50 mM) in water (40 ml) is refluxed for 15 h. After cooling the solution is made slightly acidic (pH4-5) by addition of HCl and again refluxed for 15 h. The solution is cooled, made strongly basic with sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed with water, dried and then evaporated to dryness under vacuum. The residue is purified by column chromatography using dichloromethane/methanol 93:7 as eluant. Thus pure title compound is obtained in about 60% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)(=[O:10])[CH2:8][CH3:9].[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].C(NCC)C>C(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[C:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:16])(=[O:10])[CH2:8][CH3:9]
Reactant: CCN(CC)CC
Reactant: CCC(=O)Oc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCC(=O)Oc1ccccc1C(=O)N(CC)CC
Reaction time: 1 h
Yield: 89.1 %

Procedure:
2.0 ml (23 mole) of oxalyl chloride and 0.050 ml of N,N-dimethylformamide were added, whilst ice-cooling, to a solution of 2.40 g (12.4 mole) of 2-propionyloxybenzoic acid in 24 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the solvent and excess oxalyl chloride were removed by distillation under reduced pressure, and 20 ml of methylene chloride were added to the residue. 1.36 g (13.5 mmole) of triethylamine and 986 mg (13.5 mmole) of diethylamine were then added, whilst ice-cooling, to the resulting solution, and the mixture was stirred for 1 hour. The mixture was then diluted with ethyl acetate, and the organic layer was washed with water. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 25 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and ethyl acetate ranging from 10:1 to 7:1 by volume as the eluent, to give 3.0 g (yield 97%) of 2-diethylaminocarbonylphenyl propionate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[CH3:15][N:16](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:15]#[N:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: Fc1ccc(Br)c2[nH]ccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1ccc(F)c2cc[nH]c12
Temperature: 120 °C

Procedure:
To a solution of 7-bromo-4-fluoro-1H-indole (D40) (20.0 g) in DMF (250 mL) under N2 atmosphere were added Zn(CN)2 (44.0 g) and then Pd(PPh3)4 (20.0 g). The reaction mixture was heated at 120° C. overnight. After cooling, DCM (700 mL) was added to the resulting mixture. The mixture was filtered. Then DCM (1.0 L) and H2O (1.5 L) were added to the filtrate. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with H2O, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography on silical gel to afford 4-fluoro-1H-indole-7-carbonitrile (D41) as a white solid (11.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (496 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (438 mg, yield 90%), which was then recrystallized from ethanol-water. melting point: 147–148° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(=O)OCC>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(2-pyridinyl)piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.55 (m, 4H) 4.04 (s, 2H) 6.63 (m, 1H) 6.81 (m, 1H) 7.53 (m, 2H) 8.11 (m, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 312 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1([CH:22]([CH3:24])[CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:25].C>C(O)C.C(OC(C)C)(C)C>[ClH:25].[NH2:4][C:5]1([CH:22]([CH3:24])[CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1(C(C)C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(C)C1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.18 g of 10-acetamido-10-isopropyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are dissolved in 25 ml of boiling 2N hydrochloric acid and the solution is stirred for 1 hours at boiling, cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is dissolved in 20 ml of ethanol and, after addition of decolorizing charcoal, the solution is filtered. The filter is washed with 20 ml of ethanol and the filtrate and washing are then combined, 200 ml of acetone are added and the solution is stored for 45 minutes at a temperature in the region of 5° C. The insoluble product formed is isolated by filtration, washed with 10 ml of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. The product obtained (0.6 g) is stirred in suspension in 20 ml of boiling isopropyl ether for 15 minutes and, after cooling to a temperature in the region of 20° C., the insoluble product is isolated by filtration, washed twice with 20 ml in total of isopropyl ether and dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. 0.46 g of 10-amino-10-isopropyl-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one hydrochloride is thus obtained, decomposing without melting above 250° C. (Analysis, % calculated C: 58.97, H: 5.34, Cl: 13.60, N: 17.19, O: 4.91, % found C: 59.0, H: 5.4, Cl: 13.6, N: 16.8, O: 4.9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][N:11]=1.C=O.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)=[CH:12][N:11]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(C)Cc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy}phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1.7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[ClH:13]>CC(C)=O.CCOCC>[ClH:13].[CH3:1][N:2]1[N:6]=[N:5][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1
Reactant: Cn1nnc(-c2cccnc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cn1nnc(C2CCCNC2)n1
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 12 (1.93 g, 0.012 mol) in acetone (50 ml) was added hydrogen chloride in ether until acidic reaction. The precipitate was filtered off, dried, and dissolved in methanol (25 ml). 5% palladium on charcoal (0.6 g) was added, and the mixture was shaked overnight under 3 atm. of hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. Crystallization from ethanol yielded 0.63 g (0.0031 mol, 26%) of title product. M.P. 168°-172° C. Anal. (C7H14Cl N5) C, H, N.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CCO.[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC1=Cc2ccccc2CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A mixture of 26 g (0.12 mol) of the ester obtained in Step 1 of Example 1 and 2.50 g of Pd/C 10% in 250 ml of EtOH is hydrogenated under 1 bar, at 20° C., overnight. After filtering off the catalyst and washing with ethanol, the filtrate is concentrated in vacuo to yield the expected compound in the form of a colourless oil.
Reaction SMILES: C([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH3:24])=[C:7]([Cl:27])[CH:6]=1)(=O)C.S(=O)(=O)(O)O.CO>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:27][C:7]1[CH:6]=[C:5]([OH:4])[CH:26]=[CH:25][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=[C:11]1[CH3:24]
Reactant: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Yield: 65.7 %

Procedure:
A mixture of methyl 3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (6.5 g), conc. sulfuric acid (3.0 ml) and methanol (60 ml) was refluxed under heating for 1.5 hr. The reaction mixture was diluted with chloroform (60 ml) and saturated aqueous sodium hydrogen carbonate solution was gradually added under ice-cooling. The organic layer was separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether to give methyl 3-(2-chloro-4-hydroxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (3.81 g) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18]C)[CH:13]=2)=[O:10])=[C:7]([O:22][C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si](I)(C)(C)C>C(#N)C>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:10])=[C:7]([O:22][C:23]2[CH:24]=[N:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)c2ccc(C(C)(C)C)cc2Oc2ccc(C(F)(F)F)nc2)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)Nc2cc[nH]c(=O)c2)c(Oc2ccc(C(F)(F)F)nc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 11.1 %

Procedure:
To the 4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide (137 mg, 0.3 mmol) in acetonitrile (4.9 mL) was added TMSI (93.3 μL, 0.66 mmol). The reaction was stirred at 50° C. for 12 hours. The reactions was cooled to 25° C., filtered and purified by reverse phase HPLC (10-99% ACN in Water with HCl as a modifier) to yield 4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide (141) (14.4 mg, 13%). ESI-MS m/z calc. 431.15. found 432.3 (M+1)+; Retention time: 1.78 minutes (3 minutes run).