Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CS(C)=O.C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ccccn1
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 2-(pyridin-2-yl)but-3-yn-2-ol (300 mg, 2.04 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (200 mg, 0.28 mmol, 0.50 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 3 h at 70° C. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×25 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters)): Column, XSelect Prep C18; mobile phase, water with 0.05% NH3H2O and CH3CN (23% CH3CN up to 63% in 10 min, hold 3 min); Detector, uv 254/220 nm. This resulted in 18 mg (7%) of 8-Fluoro-9-(3-hydroxy-3-pyridin-2-yl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid. LC-MS (ES, m/z): 410[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.657 (d, 1H), 8.574 (d, 1H), 8.482 (s, 1H), 7.884 (m, 2H), 7.792 (d, 1H), 7.352 (m, 1H), 7.020 (d, 1H), 6.383 (s, 1H), 4.386 (t, 2H), 3.408 (t, 2H), 1.841 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)n(-c2ccccc2)n1

Procedure:
192 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(3,4-dichlorophenyl)piperazine (95 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:23][C:21]2[O:22][C:18]([C:15]3[CH:16]=[CH:17][C:12]4[O:11][CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[C:13]=4[CH:14]=3)=[N:19][N:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CSc2nnc(-c3ccc4occ(-c5ccc(OC)cc5)c4c3)o2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([C:11]#[N:12])[CH2:6]1)=[O:4].C(Cl)C1C=CC=CC=1>CO.C([O-])(O)=O.[Na+].[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH2:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(C#N)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(O)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of (1SR,3SR,4RS)-3-cyano-4-hydroxy-cyclopentanecarboxylic acid methyl ester (185 mg) at r.t. in methanol (5 ml) under an argon atmosphere were added benzyl chloride (0.38 ml) and 10% Pd/C (50 mg). The mixture was stirred at r.t. under a hydrogen atmosphere (balloon) overnight. The catalyst was filtered off and washed with methanol. The filtrate was concentrated to leave a brown viscous oil. This was taken up in 10 ml sat. aq. NaHCO3 and extracted with CH2Cl2/MeOH 9:1 (3×10 ml) and CH2Cl2/MeOH 4:1 (10 ml). A white solid started to precipitate out of the biphasic mixture which was filtered off. The filtrate was neutralized by the addition of 1 N HCl and concentrated to leave crude (1SR,3SR,4RS)-3-aminomethyl-4-hydroxy-cyclopentane-carboxylic acid methyl ester as a light brown solid (189 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>O1CCCC1.C(Cl)Cl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[O:9][CH3:10])=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(Cl)ccc1N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
In to a stirred solution containing 10.0 grams (0.06 mole) of 4-chloro-2-methoxyaniline and 6.42 grams (0.06 mole) of triethylamine in 200 milliliters of tetrahydrofuran was added 7.65 grams (0.06 mole) of trimethylacetyl chloride in a small amount of tetrahydrofuran solvent. The resulting mixture was stirred for two hours at room temperature. Triethylamine hydrochloride precipitated and was filtered off and the filtrate vacuum stripped to give a dark liquid which was taken up in methylene chloride. This solution was washed with 2N HCl (2×100 milliliters), then with water (1×100 milliliters), dried over magnesium sulfate and solvent evaporated to give a crude product which was crystallized from hexane to give 6.82 grams (0.03 mole) of 2,2-dimethyl-N-(4-chloro-2-methoxyphenyl)propanamide as a first and second crop. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]\[CH2:24][CH:25]2[O:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:18][CH:17]=1>[C].[Pd].C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C\CC2OCCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Yield: 95.5 %

Procedure:
A mixture of (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane (5.0 g), palladium-carbon (5%, 0.1 g) and ethanol (100 ml) was subjected to catalytic hydrogenation at room 5 temperature under one atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with hexane--ethyl acetate (1:1), 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (4.8 g, 96%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:31])[S:12]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=2)[CH2:22][CH3:23])[N:17]=[CH:16]1)(=[O:14])=[O:13]>CN(C)C=O>[CH3:10][N:11]([CH3:31])[S:12]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([CH2:22][CH3:23])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:25]=2)[N:17]=[CH:16]1)(=[O:13])=[O:14]
Reactant: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1ccnc(Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1ccnc(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To sodium hydride (0.194 g, 55% in mineral oil, 4.4 mmol) in dimethylformamide (1.5 ml) was added phenol (0.418 g, 4.4 mmol) and stirring was continued for 15 min at room temperature. To this reaction mixture 4-{[(2-chloro-pyrimidin-4-yl)-ethyl-amino]-methyl}-imidazole-1-sulfonic acid dimethylamide (0.153 g, 0.44 mmol) was added. After stirring and heating to 80° C. overnight the solvent was evaporated. Water was added (5 ml) and the mixture was extracted with ethyl acetate (20 ml) twice. The combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=95:5) to yield the title compound as a colourless gum, MS (ISP): 403.4 ((M+H)+.).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([C:16](=[O:19])[NH:17][CH3:18])=[CH:9][N:8]=1)(=O)=O.[NH3:20]>CO>[NH2:20][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([C:16]([NH:17][CH3:18])=[O:19])=[CH:9][N:8]=1
Reactant: N
Reactant: CCOc1cc(COS(C)(=O)=O)ncc1C(=O)NC
Solvent: CO
Product: CCOc1cc(CN)ncc1C(=O)NC
Reaction time: 0.17 h

Procedure:
4-Ethoxy-5-methylcarbamoylpyridin-2-ylmethyl methanesulfonate (436 mg), dissolved in abs. MeOH (7 ml), was added dropwise to a methanolic ammonia solution (7.1 ml; 7N) in a microwave vessel at RT and with stirring in the course of 10 min. After standing overnight, the solvent was stripped off and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed from the acetonitrile and freeze-dried. The product was treated with saturated sodium chloride solution and rendered alkaline with potassium carbonate. After extraction with methylene chloride, the combined organic phases were dried with sodium sulfate, filtered and concentrated. 71 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80](O)=[O:81])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7])=[O:81])=[O:75])([CH3:72])([CH3:70])[CH3:71]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCN)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)c2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a solution of methyl 5-(4-amino-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.2; 5.52 mmol) in dichloro methane (5 mL) was added DIPEA (18.7 mmol) and HBTU (5.63 mmol). The mixture was stirred for 5 min at rt. 2((Tert-butoxycarbonylamino)methyl)-5-fluorobenzoic acid (4.69 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was washed with a 1M Na2CO3 solution. The aqueous phase was extracted with dichloro methane, dried and was concentrated. The crude product was purified by SiO2 column chromatography (5:1 to 1:1 hexanes:ethyl acetate) to give the target compound in 49% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[CH:5][O:4][N:3]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42]([NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-4-isoxazolamine (38.0 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (30.7 mg, 0.23 mmol), EDC (43.3 mg, 0.23 mmol) and diisopropylethylamine (0.10 ml, 0.56 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoic acid (may be prepared as described in Description 114; 80 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) and the reaction mixture was stirred at room temperature overnight. The DMF was removed on a buchi. The residue was taken up into ethyl acetate (50 ml) and washed with water (1×25 ml). The ethyl acetate layer was evaporated on a buchi under reduced pressure and the residue was purified using the MDAP. The solid obtained after concentrating the appropriate sample was taken up into ethyl acetate (50 ml) and washed with saturated bicarbonate (10 ml). The organic phase was dried (MgSO4) and evaporated to yield the title compound as a white solid. 15 mg.
Reaction SMILES: [C:1]([C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:28](=[O:32])[C:29]([OH:31])=[O:30])[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:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+:36]>>[C:1]([C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:28](=[O:32])[C:29]([O-:31])=[O:30])[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:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+:36]
Reactant: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)[O-])cc1

Procedure:
The same procedure as employed in the preparation of Example 2 but using {(4-dec-1-ynylbenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetic acid and sodium hydroxide gave the title compound as a white solid. M−(LC/MS(ESI)): 472.2. HPLC (Condition A), Rt: 5.54 min (HPLC purity: 99.6%).
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:3]=12.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[NH:15]1[CH2:14][CH2:13][CH:12]([N:8]2[C:4]3[C:3](=[N+:2]([O-:1])[CH:7]=[CH:6][CH:5]=3)[NH:10][C:9]2=[O:11])[CH2:17][CH2:16]1.[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c2ccc[n+]3[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2c(ccc[n+]2[O-])n1C1CCNCC1
Reaction time: 3 h

Procedure:
tert-Butyl 4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (45 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added at room temperature. After 3 h, the volatiles were removed in vacuo to give the title compound as its TFA salt. MS 235.2 (M+1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]2=[N:21]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N+:25]([O-:9])[CH:26]=[CH:27][C:22]2=[N:21]1
Reactant: Clc1cccc(Cl)c1-n1cc2cnccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A dried solution of mCPBA (7.2 mmol) in DCM (20 mL) was added to a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (1.28 g, 4.8 mmol) in DCM (30 mL) under nitrogen. The reaction mixture was stirred for 1 hour, warmed to room temperature, and stirred for a further 2 hours. Sodium thiosulfate (sat. aq.) was added and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated to under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a white solid (1.22 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (dd, J=1.8, 0.9 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H), 7.95 (dd, J=7.5, 1.8 Hz, 1H), 7.84 (dt, J=7.5, 1.0 Hz, 1H), 7.81-7.78 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc12
Reaction time: 1 h

Procedure:
49.8 mg (0.18 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 1.4 mL NMP. After addition of 0.06 mL triethylamine the reaction mixture is stirred for one hour. 65 mg (0.17 mmol) 6-(2,4-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester in 1.5 mL NMP and 0.02 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 38.5 mg (0.18 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with saturated NaHCO3 and stirred vigorously for one hour. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 23.4 mg (23%) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([OH:20])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:50][C:51]([NH2:58])([CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:52][NH2:53]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:58][C:51]([CH3:50])([CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:52][NH:53][C:18]([C:17]1[N:5]2[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:20]
Reactant: Cc1cc(OCCC(C)C)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)CC(C)(N)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(OCCC(C)C)c2nc(C)c(C(=O)NCC(C)(N)CC(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
175 mg (0.63 mmol) of 2,6-dimethyl-8-(3-methylbutoxy)imidazo[1,2-a]pyridine-3-carboxylic acid Example 252A were initially charged in DMF (2.2 ml), 214 mg (0.67 mmol) of TBTU, 0.28 ml (2.53 mmol) of 4-methylmorpholine and 91 mg (0.70 mmol) of rac-2,4-dimethylpentane-1,2-diamine were added and the reaction mixture stirred at RT overnight. The mixture was diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). After concentration, saturated aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 225 mg (90% of theory, purity 98%) of the target compound.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)CCOC[N:33]1[CH:37]=[CH:36][C:35]([C:38]([NH2:40])=[O:39])=[N:34]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:38]([C:35]4[CH:36]=[CH:37][NH:33][N:34]=4)=[O:39])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc(C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)c3cc[nH]n3)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
The reaction is carried out in a similar manner to Example-1 (Method-A) using 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (63 mg, 0.26 mmol). The obtained crude is diluted with DCM/TFA (1:1, 2 mL), and the mixture is stirred at rt for 1 h. Then, the solvent is removed in vacuo, and the residue is purified by preparative LC-MS to give 6.3 mg (11% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.Cl.[NH:22]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:18]1([CH2:17][O:16][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:25]4[CH:26]=[N:22][NH:23][CH:24]=4)[CH:7]=3)=[CH:15][C:12]=2[C:13]#[N:14])[CH2:20][CH2:19]1
Reactant: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OCC1CC1
Reactant: Nc1cn[nH]c1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#Cc1cc(-c2ccnc(Nc3cn[nH]c3)c2)ccc1OCC1CC1
Yield: 91.4 %

Procedure:
A solution of 5-(2-chloropyridin-4-yl)-2-cyclopropylmethoxybenzonitrile (0.25 g, 0.0878 mmol) in t-butanol (5 ml) is degassed with nitrogen for 5 min. 1H-Pyrazol-4-ylamine hydrochloride (0.12 g, 1.08 mmol), Josiphos (24.3 mg, 0.00439 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40.0 mg, 0.00439 mmol) is then added. A solution of 1.6M lithium bis(trimethylsilyl)amide in THF (0.35 g, 2.1 mmol) is added dropwise. The mixture is irradiated in the microwave at 140° C. for 2 h. 30 ml of water are then added, and the mixture is filtered. The crude product is purified by chromatography, giving 26.6 mg of the desired product as brown solid;