Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:14][CH:13]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(OC)c1
Temperature: 130 °C

Procedure:
To a 50 mL flask containing a stir bar were added 2-methoxy-4-bromobenzonitrile (0.30 g, 1.4 mmol), palladium tetrakis (82 mg, 0.071 mmol), allyltri-n-butyltin (0.88 mL, 2.8 mmol), and lithium chloride (0.120 g, 2.83 mmol). The resulting mixture was then dissolved in anhydrous toluene (16 mL); the flask was placed in an oil bath and heated at 130° C. LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The flask was taken out of the oil bath and cooled to room temperature. To the flask was poured EtOAc (40 mL) and the mixture was transferred into a reparatory funnel and washed with aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then dissolved in DCM and absorbed into silica gel. The silica gel was then loaded onto a silica column for separation with the solvent systems of hexanes/EtOAc (1/0.3); this gave 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile. LC-MS (IE, m/z): 174 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=O)[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:15][NH:16][NH2:17]>CCO>[CH2:9]([O:8][C:6]([C:5]1[N:16]([CH3:15])[N:17]=[C:3]([C:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5,5-dimethyl-2,4-dioxo-hexanoate (1.02 g, 5.09 mmol) was dissolved in absolute EtOH (20 mL). CH3NHNH2 (0.270 mL, 5.09 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was warmed to 80° C. for 4 h, and then cooled to room temperature. The solvent was removed under reduced pressure, and the resulting residue was chromatographed using a 70-g pre-packed SiO2 column eluting with 1:19 EtOAc-hexanes to yield the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 6.68 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 4.12 (s, 3H), 1.38 (t, J=7.1 Hz, 3H), 1.30 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)[N:15]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:13][C:14]1[C:19]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=[C:16]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=2)[N:15]=1
Reactant: CCCCCc1ccc(Br)cc1
Reactant: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)c(F)n2)cc1

Procedure:
A solution of 40 mmol of 1 -bromo-4-pentylbenzene in 90 ml of toluene is admixed with 44 mmol of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid, 45 ml of ethanol, a solution of 80 mmol of sodium carbonate in 45 ml of water and 0.4 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 5 h. After cooling, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are washed with water and saturated sodium chloride solution and dried with magnesium sulfate. The solvents are then removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane/dichloromethane 1:1 as eluent and recrystallization from acetonitrile/acetone 1:1, giving 2-fluoro-6-(4-nonylphenyl)-3-(4-pentylphenyl)pyridine.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C.Cl.[F:46][C:47]1([F:52])[CH2:51][CH2:50][NH:49][CH2:48]1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][C:47]([F:52])([F:46])[CH2:48]4)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: O=C(Cl)CCl
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CN2CCC(F)(F)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (47 μl) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 1 hour. 3,3-Difluoropyrrolidine hydrochloride (Synthetic Letters, 1995, 1, 55-57; 328 mg) was added, and the solution stirred for 1 hour before being washed with saturated aqueous sodium bicarbonate (10 ml) and purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride methanol (100/0 to 9515) to give a foam. This was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product (102 mg). NMR Spectrum (DMSO d6) 1.45-1.57 (m, 1H), 1.73-1.95 (m, 2H), 1.98-2.18 (m, 2H), 2.18-2.33 (m, 1H), 2.63-2.75 (m, 1H), 2.77-2.85 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.19 (m, 1H), 3.21-3.29 (m, 1H), 3.37-3.50 (m, 2H), 3.52-3.70 (m, 2H), 3.77-3.99 (m, 4H), 4.63 (m, 1H), 7.21-7.29 (m, 2H), 7.47-7.57 (m, 2H), 7.87 (d, 1H), 8.39 (s, 1H), 9.55 (d, 1H); Mass Spectrum: (M+H)+ 550.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:26]
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) in DMF (3 ml) was added 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 45 mg, 0.204 mmol), TBTU (78 mg, 0.245 mmol) and DIPEA (40 mg, 0.306 mmol). The reaction was stirred at room temperature for 2 hours and was then diluted with water (25 ml) and extracted with ethyl acetate (3×30 ml). The organics were washed with water (25 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography (silica, 0-45% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[N:5]=[CH:4][N:3]=1.[CH3:12][CH:13](O)[CH3:14].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][CH:13]([O:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:1][CH:16]([CH3:21])[CH3:17])[N:3]=[CH:4][N:5]=1)[CH3:14]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1c(O)ncnc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)Oc1ncnc(OC(C)C)c1[N+](=O)[O-]
Yield: 32.5 %

Procedure:
To a mixture of 6.28 g of 4, 6-dihydroxy-5-nitropyrimidine, 6.00 g of 2-propanol, 10.5 g of triphenylphosphine and 80 ml of tetrahydrofuran was added 6.97 g of diethyl azodicarboxylate at room temperature with stirring, and the resultant mixture was stirred for 2 hours, mixed with 10.5 g of triphenylphosphine and 6.97 g of diethyl azodicarboxylate, stirred for 11 hours, again mixed with 10.5 g of triphenylphosphine and 6.97 g of diethyl azodicarboxylate and stirred for further 11 hours. The precipitate was filtered off, and the filtrate was concentrated in vacuo. The residue was mixed with ether, and the insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate-n-hexane (1:14) to give 3.13 g of 4, 6-di (1-methylethoxy)-5-nitropyrimidine.
Reaction SMILES: C1([Se][Se]C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].C(O)(=[O:19])C.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22].[CH2:27]([OH:29])[CH3:28]>>[C@@H:21]12[O:23][CH2:26][C@@H:25]([O:24]1)[C@H:27]([OH:29])[CH2:28][C:22]2=[O:19]
Reactant: CCOC(C)=O
Reactant: CCO
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc([Se][Se]c2ccccc2)cc1
Product: O=C1C[C@@H](O)[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.6 %

Procedure:
0.47 g (1.50 mmol) of diphenyl diselenide dissolved in 7.5 ml of dry ethanol and 0.11 g (3.00 mmol) of sodium borohydride was gradually added thereto at room temperature. After the reaction mixture was stirred for 5 minutes, 11.6 ml of acetic acid was added to the reaction mixture while ice-cooling. Then, 0.16 g (1.00 mmol of 1,6:3,4-dianhydro-β-D-lyxo-hexopyranos-2-ulose monohydrate represented by the above formula [5'] dissolved in 8 ml of a dry ethanol was added dropwise thereto. After the reaction mixture was stirred for 2 hours while ice-cooling, a temperature thereof was raised to room temperature and diluted by adding 78 ml of ethyl acetate. After a solvent was removed from the reaction solution under reduced pressure, the residue was purified by means of silica gel column chromatography (hexane: ethyl acetate=1:2), thereby obtaining 0.12 g (yield: 80.6%) of 1,6-anhydro-3-deoxy-β-D-threo-hexopyranos-2-ulose represented by the following formula [6]. This was recrystallized from a hexane-diethyl ether mixed solvent. ##STR15##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[C:40]([CH:44]=[O:45])[CH:41]=[N:42][CH:43]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[C:40]([CH:44]=[O:45])[CH:41]=[N:42][CH:43]=3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=Cc1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(C=O)c3)cc12
Temperature: 80 °C
Yield: 55.5 %

Procedure:
3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 9.91 mmol), commercial 5-bromo-pyridine-3-carbaldehyde 1.84 g, 9.91 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (405 mg, 0.495 mmol) were combined in a vial under nitrogen and dissolved in acetonitrile (25 mL) and tetrahydrofuran (25 mL). Saturated sodium bicarbonate (25 mL) was added and the system was purged with nitrogen gas. The reaction mixture was capped and heated for 15 h at 80° C. The cooled mixture was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridine-3-carbaldehyde (2.66 g, 55.7%). MS: m/z 484 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([O:9]C)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:3]1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Temperature: 65 °C

Procedure:
To a solution of methyl (+−)-trans-4-methylene-2-phenylcyclopentanoate prepared as in Step A (28.4 g, 131 mmol) in methanol (400 mL) was added 5N sodium hydroxide (131 mL, 656 mmol). The reaction was heated at 65° C. for 1 h then cooled and concentrated. The residue was diluted with water, acidified with 2M hydrochloric acid and extracted twice with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo to give the crude title acid (27.2 g) which was used directly in Step B.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])(C)[CH3:2].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]1(C)C=CC=CC=1.CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:20])[NH:8][S:7]2(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: BrCc1ccccc1
Reactant: CC(C)C1NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Yield: 72 %

Procedure:
Eight grams (44.94 mmol) of 4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (which was dissolved in methanol, brought to pH 5 with ion exchange resin, filtered, and concentrated in vacuo to remove methanol), phenylmethyl bromide (8.09 g, 47.2 mmol), and tetrabutylammonium bromide (1.5 g, 4.66 mmol) suspended in toluene/DMF (200 ml/50 ml) was allowed to react at 130° C. for 30 hours. The resulting mixture was cooled, the excess toluene was concentrated in vacuo, and the residue was diluted with 200 ml of water and extracted with ether/ethyl acetate (4:1, 700 ml). The organic layer was washed with water and brine, dried and concentrated in vacuo to yield a residue which was purified by flash chromatography to afford 8.6 g (72%) of 2-phenylmethyl-4-isopropyl-1,2,5-thiadiazol-idin-3-one 1,1-dioxide (Formula IX: R1 =H; R2 =isopropyl) as a solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([NH:24][CH2:21][CH2:22][CH3:23])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: CCCN
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Product: CCCNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Reaction time: 36 h
Yield: 72.8 %

Procedure:
A mixture of compound 6 (22.5 mg, 0.056 mmol) and n-propylamine (2 mL) was stirred at 85° C. for 36 h. After evaporation of volatiles, the residue was purified by preparative TLC (chloroform-methanol, 20:1) to give compound 13 (17.3 mg, 72.8%) as a slightly yellow solid. 1H NMR (DMSO-d6) δ 0.85 (pseudo t, J=7.5 and 7.3 Hz, 3 H, CH3), 1.47 (sextet, J=7.2 Hz, 2 H, CH2), 3.30 (m, 2 H, CH2), 3.54 (s, 3 H, 9-CH3), 4.58 (br s, 2 H, CH2), 6.33 (br s, 1 H, exchangeable with D2O, NH), 7.10 (pseudo t, J=8.0 and 7.7 Hz, 1 H, H-16), 7.36 (d, J=7.7 Hz, 1 H, H-17), 7.57 (d, J=8.2 Hz, 1 H, H-15), 7.66 (s, 1 H, H-13), 7.72 (s, 1 H, H-8), 7.80 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Br)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C]=O.[C:41]([O:44][CH2:45]C)(=[O:43])C>CO.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:41]([O:44][CH3:45])=[O:43])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COc1c(NC(=O)c2cc3cccc(Br)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)n(C)c12

Procedure:
Argon is piped for 10 minutes through a suspension of 18.8 g 7-bromo-1-methyl-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide in 250 ml of methanol and 50 ml N,N-dimethylformamide. Then 7.2 ml triethylamine and 2.3 g [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex are added and 2 bar of carbon monoxide are compressed in for 15 hours at 80° C. Then the solvents are eliminated in vacuo, the residue is taken up in ethyl acetate and washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is extracted from methanol. The solid is suction filtered, washed with a little methanol and dried.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][OH:33])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][OH:33])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCO)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCO)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxypropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (17 mg, 28.9 μmol) in dichloromethane (4.00 mL) was added TFA (1480 mg, 1.0 mL, Eq 450), the reaction mixture turned orange and was stirred at 25° C. for 24 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to an off-white solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, light yellow solid was separated by filtration and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxypropyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 26.2 μmol, 90.6%). MS (M+H)+=459; 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.79-7.94 (m, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.62-4.68 (m, 1H), 4.59 (t, J=6.8 Hz, 2H), 3.40-3.51 (m, 2H), 2.06 (t, J=6.2 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])[N:6]=[C:5]([N:23]([CH3:25])[CH3:24])[N:4]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C>[Br:26][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([N:23]([CH3:25])[CH3:24])=[N:6][C:7]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22]
Reactant: COCOCCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCOCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Temperature: 23 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 1.41 g (3.99 mmol) of 4-methoxy-6-(10-(methoxymethoxy)decyl)-N,N-dimethylpyrimidin-2-amine in 10 mL of acetonitrile were added 852 mg (4.79 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. and protected from light for 5 h. The reaction mixture was concentrated under diminished pressure and the residue was dissolved into 100 mL of ethyl acetate. The organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 910 mg (53%); silica gel TLC Rf 0.65 (9:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.31-1.26 (br m, 10H), 1.54-1.64 (m, 4H), 2.67 (dd, 2H, J=7.6, 7.6 Hz), 3.11 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.92 (s, 3H) and 4.59 (s, 2H); 13C-NMR (CDCL3) δ 26.18, 27.59, 29.34, 29.40, 29.40, 29.47, 29.55, 29.72, 36.68, 36.93, 53.96, 55.04, 67.85, 91.16, 96.35, 160.06, 165.05 and 169.04; mass spectrum (APCI+), m/z 432.1857 (M+H) (C19H35N3O3Br requires 432.1862).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[C:5]([F:16])=[CH:4][C:3]=1[F:17].CCN=C=NCCCN(C)C.Cl.[CH2:30]([O:32][C:33](=[O:43])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:43])[CH2:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13](=[O:15])[CH2:12][CH2:11][C:9]1[S:10][C:6]2[C:5]([F:16])=[CH:4][C:3]([F:17])=[C:2]([F:1])[C:7]=2[N:8]=1)[CH3:31]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
To methylene chloride (10 ml) was added 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) obtained in Example 3-i), WSC.HCl (422 mg, 2.2 mmol) and N-benzylglycine ethyl ester (386 mg, 2 mmol) and the mixture was stirred for 15 hours at room temperature. The reaction mixture was washed with 7% hydrochloric acid and water successively. The organic layer was dried and evaporated. The resulting residue was purified on a silica gel column to give N-benzyl-N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-glycine ethyl ester (680 mg, 78%) as an oil.
Reaction SMILES: CN1CCN([C:8]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16](=[CH2:23])[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)CC1.[OH-:24].[Na+]>Cl>[CH2:23]=[C:16]1[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=2
Reactant: [OH-]
Reactant: C=C1c2cnccc2C=C(N2CCN(C)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Product: C=C1c2cnccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from Step D (10.76 g.) and 3N HCl (150 ml.) is stirred at room temperature for approximately 24 hours. The dark brown solution is made alkaline by the addition of 20% NaOH solution and extracted with methylene chloride. The extracts are washed with H2O, saturated NaCl solution and dried (Na2SO4). Removal of the solvent in vacuo followed by trituration with petroleum ether (30°-60°) provides 6.2 g., m.p. 98°-110° C.