Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)[CH2:40][CH2:39]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncccc4c3O2)cc1
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CC3CCN(CC4COc5ccc6ncccc6c5O4)CC3)c2c1
Temperature: 77.5 °C

Procedure:
(2R)-2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.46 g, 1.24 mmole) and 5-fluoro-3-(4-piperidinylmethyl)-1H-indole (1.00 g, 4.32 mmole) were combined in 40 mL of DMSO and heated at 75-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated sodium bicarbonate solution. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate and concentrated to an oil in vacuum. This was column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute 0.200 g of the product as a yellow oil. The oil was crystallized from isopropanol with the addition of 0.040 g of oxalic acid to give 0.107 g of the (S)-enantiomer of the title compound as a light red solid (m.p. 184° C.), which contained both water and isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1>CO.[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 66 %

Procedure:
13.5 g. ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate, dissolved in 110 ml methanol and 39 ml 2 N aqueous potassium hydroxide solution, are maintained at reflux temperature for 12 hours. The solution is then evaporated in a vacuum. After dilution with water, it is extracted with diethyl ether, the aqueous phase is filtered, with the addition of active charcoal, and the filtrate is acidified. There are obtained 11.7 g (95% of theory) of acid which is recrystallized from 25 ml glacial acetic acid. There are obtained 8.2 g (66% of theory) 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetic acid; m.p. 186°-187° C. From the mother liquor, there is obtained a further 1.9 g (15% of theory) of this acid, which has a melting point of 182°-183° C.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[O:9][C:10]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([Br:19])=[CH:13][C:11]=2[CH:12]=1)(=[O:7])C.Cl>O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:10]2[O:9][C:8]([C:5]([OH:7])=[O:1])=[CH:12][C:11]=2[CH:13]=1
Reactant: [OH-]
Reactant: COc1cc(Br)cc2cc(C(C)=O)oc12
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(Br)cc2cc(C(=O)O)oc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 107.6 ml of 5N sodium hydroxide aqueous solution was added dropwise 26.8 g of bromine at a temperature of -5° C. or below. To this was further added dropwise and slowly a 100 ml dioxane solution containing 15.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran obtained in the above step a). After completion of the dropwise addition, the temperature of the resulting reaction solution was increased gradually to 60° C. and then stirred for 30 minutes. After cooling, the resulting reaction solution was adjusted to pH 2 with concentrated hydrochloric acid and then extracted with ethyl acetate. The resulting organic layer was concentrated to dryness, and crystals thus precipitated were collected by filtration to obtain 5-bromo-7-methoxy-2-benzofurancarboxylic acid. The thus obtained crystals were suspended in 200 ml of ethanol, and 10 ml of thionyl chloride was added dropwise to the suspension with stirring at room temperature. The resulting reaction solution was refluxed under heating for 2 hours. After cooling, the thus treated reaction solution was neutralized with saturated sodium bicarbonate aqueous solution, and then mixed with water to collect precipitated crystals by filtration. The crystals thus collected were purified by silica gel column chromatography using chloroform as an eluant to obtain 11.33 g of ethyl 5-bromo-7-methoxy-2-benzofurancarboxylate.
Reaction SMILES: C([O:4][C@@H:5]([C@@H:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+]>CO.O>[CH:9]1([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[C@@H:12]([N:16]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11]1
Reactant: CCC[C@@H]([C@H](OC(C)=O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 17 h
Yield: 74.1 %

Procedure:
(2S,3S)-1-(cyclopropylamino)-3-(dibenzylamino)-1-oxohexan-2-yl acetate (17 g) was dissolved in methanol (120 mL) at room temperature and the resulting solution cooled to 0-5° C. To this solution was added a previously prepared 1.1-M solution of sodium hydroxide by dissolving solid NaOH (2.49 g) in water (55 mL), which was then added to the reaction mixture at 0-5° C. The reaction was warmed to room temperature (25-30° C.) and stirred at this temperature for 16-18 hours. The reaction mixture was monitored by TLC for the disappearance of starting material. Once TLC indicated that the reaction was complete, the solvent was removed by distillation under reduced pressure, keeping the temperature below 45° C. Ethyl acetate (2.5 L) was added and the resulting solution was stirred for 20-30 minutes. The organic layer was washed with water (500 mL), followed by an aqueous solution of sodium chloride (brine; 300 mL). The organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated under reduced pressure, keeping the temperature below 40° C. n-Hexane (100 mL) was added, and the slurry was stirred for one hour at 25-30° C. The resulting solid was filtered off, then dried under reduced pressure to provide (2S,3S)—N-cyclopropyl-3-(dibenzylamino)-2-hydroxyhexanamide (11.3 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]
Reactant: CSc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc2cnsc2c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc3cnsc23)c(F)c1
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
To a solution of 2-fluoro-4-methylsulfanyl-phenylamine (628 mg, 4.0 mmol) in anhydrous THF (15 mL) at −78° C. was added a 1.0M solution of LHMDS in hexanes (6.0 mL, 6.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (394 mg, 2.0 mmol) in anhydrous THF (15 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 minutes, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous HCl (ca. 50 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, MeOH in DCM) to give the title compound as a brown solid (200 mg, 30%). LCMS (method B): RT=3.67 min, [M+H]+=335
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:26][N:27]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([CH3:26])[CH2:28]1)=[O:7]
Reactant: CN1CC[C@@H](N)C1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 374 mg, 1.73 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (0.96 mL, 5.54 mmol) added. The mixture was cooled in an ice/water bath and (3R)-1-methylpyrrolidin-3-amine dihydrochloride (Intermediate 184; 300 mg, 1.73 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hour. The mixture was washed with brine, 2N NaOH(aq), dried with MgSO4 and evaporated to yield the title compound as a brown solid (227 mg, 46.9%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to the procedure of Example 4, as an off-white solid: mp 193-194° C.; 1H-NMR (CDCl3) d 9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calcd. For C18H18N2O4.0.3H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[CH:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[C:33][C:2]2[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CCOC(=O)CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C
Yield: 94.3 %

Procedure:
A solution ethyl {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}acetate (216 mg, 0.52 mmol) and 3-hydroxyphenylacetylene (0.052 mL, 0.79 mmol) in anhydrous DMF (3 mL) was treated with triethylamine (0.22 mL, 1.58 mmol). The reaction mixture was degassed (alternating vacuum and argon) and PdCl2(Ph3P)2 (36.9 mg, 0.052 mmol) and triphenylphosphine (3.4 mg, 0.013 mmol) were added. The reaction mixture was degassed (alternating vacuum and argon) and placed under an atmosphere of 1:3 Argon/hydrogen atmosphere. Copper(1+) iodide was added and the reaction mixture was heated at 60° C. for 50 min. The brown reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was collected and washed further with saturated aqueous NaHCO3 (1×), brine (1×), and dried over anhydrous Na2SO4. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a light yellow solid (220 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (0.37 g, 2.575 mmol), and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.52 g, 76%) as a yellow solid. 1H NMR (DMSO-d6) δ 2.17 (s, 6H), 2.42 (t, 2H, J=6.6 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.79 (s, 2H), 7.45 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=2.7 Hz), 7.96 (dd, 1H, J=2.4, 9.0 Hz); ESI-MS (m/z, %): 266 (MH+, 100), 221 (66).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>>[ClH:47].[ClH:47].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH:45][C:28](=[O:30])[CH2:27][O:26][C:25]1[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:21][C:20]2[C:15]([NH:14][C:11]3[S:12][CH:13]=[C:9]([CH3:8])[N:10]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)O)c2)n1
Reactant: CN(C)CCN
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCCN(C)C)c2)n1
Yield: 56.1 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) ethyl chloroformate (0.035 mL, 0.36 mmol) and N1,N1-dimethylethane-1,2-diamine (0.079 mL, 0.72 mmol) were reacted according to the method of Example 30 to provide N-(2-(dimethylamino)ethyl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamide dihydrochloride (43.8 mg, 56.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.54 (bs, 1H), 10.76 (bs, 1H), 8.54 (t, 1H), 8.00 (d, 1H), 7.66 (d, 1H), 7.32 (m, 2H), 7.18 (m, 2H), 6.97 (dd, 1H), 6.93 (s, 1H), 5.34 (s, 2H), 4.60 (s, 2H), 3.53 (q, 2H), 3.19 (q, 2H), 2.76 (s, 6H), 2.35 (s, 3H). Mass spectrum (apci) m/z 442.1 (M+H-2HCl).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1)[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH2:31][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:21]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1
Yield: 56.2 %

Procedure:
Compound 7 was prepared using the same method as used in Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([Cl:19])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.1 %

Procedure:
To a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetic acid (833 mg, 3.03 mmol) in dichloromethane (10 mL) were added oxalyl chloride (0.29 mL, 3.33 mmol) and dimethylformamide (1 drop) under argon atmosphere. The mixture was stirred for 3.5 hours at room temperature, then was concentrated to dryness under reduced pressure. Dichloroethane (15 mL) was added, and resulting solution was back evaporated to dryness to obtain crude (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (917 mg).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:4]=1)#[N:2].C[O-].[Na+].[Cl-].[NH4+:24].C(O)(=O)C>CO>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([C:1](=[NH:24])[NH2:2])=[N:4]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
108.00 g (0.43 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (example I, step 4) are dissolved in one liter of methanol and added dropwise to a solution of 94.73 g (1.67 mol; purity: 95%) of sodium methoxide in 3 l of methanol. After stirring at RT for 2 hours, 28.83 g (0.54 mol) of ammonium chloride are added, and subsequently 100.03 g (1.67 mol) of glacial acetic acid are added dropwise. This solution is stirred under reflux overnight. The solvent is removed in vacuo, the residue is twice suspended in acetone and the insoluble solid is filtered off with suction. The latter is dissolved in 1.5 l of ethyl acetate, and 590 ml of an aqueous 20% strength sodium carbonate solution are added. Stirring for 20 minutes is followed by dilution with 200 ml of 1N sodium hydroxide solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent is removed in vacuo. 99.10 g (86% of theory) of the product are obtained.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCc2cccc(C(F)(F)F)c2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 1-[3-(trifluoromethyl)phenyl]methanamine (45.58 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 75 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 3.56 (s, 2H), 4.61 (s, 2H), 7.16 (t, J=75.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.36-7.51 (m, 2H), 7.57-7.65 (m, 3H), 7.71-7.77 (m, 2H), 7.83 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.82-8.88 (m, 1H); APCI-MS (m/z) 580.29 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Yield: 60.4 %

Procedure:
A solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.6 g 2.53 mmol) and NBS (0.5 g 2.8 mmol) in DMF (10 ml) was stirred at room temperature for 2 hr. The reaction was poured into water (100 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with water (30 ml), brine (30 ml), dried and purified by biotage chromatography. Elution with cyclohexane/ethyl acetate (20:1) gave the title compound as a white solid (0.483 g 61%). NMR: (CDCl3): δ 7.21 (2H, t) 7.30 (1H, dd) 7.62 (1H, dd) 8.06 (2H, m) 8.80 (1H, s).