Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](=O)([O:10]C)[O:8][CH3:9]>C[O-].[Na+].CO>[C:7](=[O:10])([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:8][CH3:9]
Reactant: OCC(F)(F)F
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)F
Temperature: 100 °C
Yield: 32.8 %

Procedure:
In a flask (3-liter volume) equipped with 10 distillation columns, 2,2,2-trifluoroethanol (790 g, 7.9 ml), dimethyl carbonate (2140 g, 23.7 mol) and a 28% sodium methoxide/methanol solution (15.3 g) were charged. The flask was heated to 100° C. to allow the starting materials to react for 30 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,2-trifluoroethyl carbonate as a colorless liquid (410 g, yield 33%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 3 and FIG. 4 respectively and the mass spectrometry spectrum (M/e=158).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:31])([C:14]2[S:15][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:11]1([C:14]2[S:15][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(COc3ccc(S(C)(=O)=O)cc3)s2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(OCc2cnc(C3(F)CCNCC3)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 89, 1.30 g, 2.76 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (10 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to afford the desired product as a white solid.
Reaction SMILES: BrBr.[CH2:3]([C:6]#[N:7])[CH:4]=[CH2:5].BrC(CBr)CC#N.[C:15]1([C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18])[OH:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:16]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[O:18][CH2:5][CH:4]1[CH2:3][C:6]#[N:7]
Reactant: Oc1ccccc1O
Reactant: C=CCC#N
Agent: BrBr
Agent: N#CCC(Br)CBr
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: N#CCC1COc2ccccc2O1
Reaction time: 1.5 h

Procedure:
The starting material is prepared as follows: To the solution of 1,134 g of bromine in 1,400 ml of ethyl acetate 472 g of allyl cyanide are added dropwise while stirring for 90 minutes at -10°-0°. The resulting solution of 3,4-dibromobutyronitrile is added all at once to the solution prepared from 705 g of catechol and 1,987 g of anhydrous potassium carbonate in 5,000 ml of refluxing ethyl acetate, while stirring at 35° under nitrogen. The mixture is refluxed for 4 hours and stirred overnight at room temperature. It is filtered, the residue washed with 2,000 ml of ethyl acetate, the filtrate evaporated, the residue distilled and the fraction boiling at 138°/1.4-131°/1.1 mm Hg collected, to yield the 1,4-benzodioxan-2-yl-acetonitrile.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([O:24]C)=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)C)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Methyl 4-(2-iso-propoxypyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (2.04 g, 5.7 mmol) was suspended in MeOH (24 mL). Into this solution was added a solution of aqueous 2M sodium hydroxide (6.0 mL, 12 mmol) and the reaction stirred at 60° C. for 1 hour. The solution was cooled in an ice-bath and concentrated hydrochloric acid added until the solution reached pH 5. The precipitate was collected, washed with water and dried to yield off-white solid (1.50 g, 76%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC(=O)[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1)(C)(C)C.C(OC(=O)NC1CCCC(B2OC(C)(C)C(C)(C)O2)=C1)(C)(C)C>>[NH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][C:33]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[C:5]=3[O:4][CH:3]=2)=[CH:32]1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: CC(C)(C)OC(=O)NC1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CC(N)CCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting material 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and the mixture of [3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester and [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-2-enyl]-carbamic acid tert-butyl ester. 1H-NMR (CD3OD, 400 MHz): δ=1.48-1.82 (m, 2H), 1.88 (d, 3H), 1.91-2.16 (m, 2H), 2.38 (d, J=5.3 Hz, 2H), 3.72 (br. s., 1H), 6.21 (br. s., 1H), 6.48 (qd, J=6.7, 2.5 Hz, 1H), 7.02-7.14 (m, 1H), 7.38 (dd, J=8.8, 4.8 Hz, 1H), 7.63 (s, 1H), 8.22 (s, 1H). MS (ES+): m/z 436.03 (MH+, 35Cl, 37Cl), 437.96 (MH+, 37Cl, 37Cl). HPLC: tR=2.38 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:17][O:16][C:14]([C@@H:9]1[CH2:10][C@H:11]([NH:13][CH:22]2[CH2:23][CH2:24][C:19]([CH3:26])([CH3:18])[CH2:20][CH2:21]2)[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:15]
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To methyl (2S,4S)-1-Boc-4-aminopyrrolidine-2-carboxylate (1.07 g, 4.38 mmol) and dimethylcyclohexanone (0.66 g, 5.25 mmol) in DCE (20 mL) was added dropwise NaBH(OAc) (1.39 g, 6.57 mmol) at rt. The reaction mixture was stirred at rt for 4 h, a saturated NaHCO3 aqueous solution was added, and extracted with DCM (50 mL×2) and EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The obtained residue was purified by column chromatography (eluent, EtOAc/Hex=1/2) to give the title compound (1.16 g, 75%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH:14]1[C:23]2[O:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[CH2:28][NH2:29].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:29]([CH2:28][C:15]1[CH:16]=[CH:17][C:18]3[O:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[O:22][C:23]=3[CH:14]=1)[CH2:11]2
Reactant: NCc1ccc2c(c1)Oc1ccccc1O2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc2c(c1)Oc1ccccc1O2
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.148 g, 0.6 mmol), C-dibenzo[1,4]dioxin-2-yl-methylamine (0.213 g, 1.0 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-Chloro-2-dibenzo[1,4]dioxin-2-ylmethyl-2,3-dihydro-isoindol-1-one (0.023 g, 13%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.65 (s, 2H), 6.85 (m, 8H), 7.40 (t, 2H). GC-MS: m/z 363 (M)+.
Reaction SMILES: CC1C(C[N:8]([CH2:10][C:11]2[S:15][CH:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:28]3[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]3)[CH:12]=2)[CH3:9])=C(C)NN=1.[CH3:40][C:41]1C(CNC)=C(C)N[N:42]=1>>[C:41]([CH2:40][N:8]([CH2:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:30][CH2:29]2)[CH:12]=1)[CH3:9])#[N:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5c(C)n[nH]c5C)c4)cc23)CC1
Reactant: CNCc1c(C)n[nH]c1C
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC#N)c4)cc23)CC1
Yield: 12.7 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting (methylamino)acetonitrile (320 μmol) for 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine to afford 6.36 mg of the title compound (12.7%).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[I:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: CN
Reactant: Clc1ncncc1I
Product: CNc1ncncc1I
Yield: 78 %

Procedure:
A solution of 4-chloro-5-iodopyrimidine 4A (2.03 g, 8.44 mmol) in 40% aqueous MeNH2 solution was stirred at RT for 17 h. The mixture was then extracted with DCM (2×150 ml). The combined organic phase were dried concentrated to give 5-iodo-4-methylaminopyrimidine 4B (1.55 g, 78%) as an orange solid which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([C:9](=[O:11])[CH3:10])=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>CC(C)=O>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([C:9](=[O:11])[CH3:10])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1noc2cc(O)ccc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1noc2cc(OCc3cccc(C(F)(F)F)c3)ccc12

Procedure:
2 g of 1-(6-hydroxy-1,2-benzisoxazol-3-yl)ethanone are dissolved in 20 ml of acetone, 2.1 g of potassium carbonate are added and then 3 g of 1-(bromomethyl)-3-(trifluoromethyl)benzene are added dropwise. The reaction mixture is then refluxed for 1 h. After cooling and filtration and concentrating the filtrate under vacuum, the crude product is taken up in ethyl acetate, the organic phase is washed once with water and once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. Recrystallistion from ethyl acetate/hexane gives 1-(6-[3-(trifluoromethyl)benzyloxy]-1,2-benzisoxazol-3-yl)ethanone having a melting point of 130°-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>[Pd].C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)cc1C#N

Procedure:
A mixture of 2-methyl-5-nitrobenzonitrile (25.0 g, 154 mmol), 10% palladium on charcoal (2.5 g) ethyl acetate (150 mL) and ethanol (150 mL) is stirred under an atmosphere of hydrogen. The catalyst is removed by filtration through a pad of celite and the filtrate is concentrated to give 5-amino-2-methylbenzonitrile (also see, Scholz, D. et al. J. Med. Chem., 41, 1050-1059 (1998)) (19.6 g, 96%) as a tan solid. MS: m/e=133 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:43][C:44]1[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:45]=1[CH2:51][CH2:52]O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:52][CH2:51][C:45]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:44]=2[Cl:43])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2 g (13.1 mmol) of 3-hydroxybenzoic acid methyl ester and 4.75 g (18.1 mmol) of triphenylphosphine were dissolved in 48 ml of anhydrous tetrahydrofuran. The solution was cooled to 0° C. and a solution of 3.04 g (17.5 mmol) DEAD in 7 ml of anhydrous tetrahydrofuran was added dropwise over 20 min. The solution was stirred at RT for 45 min. and a solution of 2.76 g (14.5 mmol) of 2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous tetrahydrofuran was added. The reaction was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (4/1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](Cl)=[N:24][CH:25]=1)=[O:19].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:28])[F:29])=[N:22][C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=3[CH3:9])[CH2:11][CH2:12]2)=[N:24][CH:25]=1)=[O:19]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1c(Cl)nnc(N2CCNCC2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a roundbottom flask is added 3-chloro-4,5-dimethyl-6-piperazin-1-yl-pyridazine (1 g, 4.41 mmol), 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (2.12 g, 8.82 mmol) and diisopropylethylamine (2.3 mL, 13.23 mmol) in a dioxane (9 mL) solution and stirred for 18 h at room temperature. Filter the reaction mixture and rinse with water and ethylacetate to give 1.35 g of 2-[4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (71%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=1Br.Cl>[Cu]Br.O1CCOCC1>[F:22][C:20]1[CH:19]=[C:18]([F:23])[C:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: COc1cc(F)cc(F)c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1OC
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
Diethyl malonate (0.49 mol) was added to a mixture of sodium hydride (0.51 mol) and 1,4-dioxane (140 ml) at 60° C. within 2 hours. The mixture was stirred for 10 minutes at 60° C. and copper (I) bromide (0.05 mol) was added. After 15 minutes, a mixture of 2-methoxy-4,6-difluorobromobenzene (0.25 mol) and 1,4-dioxane (10 ml) was added. The reaction mixture was stirred at about 100° C. for about 15 hours. After cooling to about 15 to 20° C. 35 ml of 12N hydrochloric acid were added. The precipitate was filtered off. The filtrate was extracted with diethyl ether. The organic phase was separated, dried and filtered. The filtrate was evaporated to yield 44 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38]([O:40]C)=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:36])([F:37])[F:35])[C:25]([C:38]([OH:40])=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
215 mg (0.36 mmol) of the compound from Example 139 were dissolved in 3 ml of THF and 3 ml of methanol, and 0.36 ml of 2 N aqueous sodium hydroxide solution was added. The mixture was stirred at 80° C. for 16 h. For work-up, the mixture was diluted with 10 ml of water and extracted twice with in each case 10 ml of ethyl acetate. The aqueous phase was acidified with 1 N hydrochloric acid and once more extracted with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum. This gave 222 mg (quant.) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11](=[O:13])[CH3:12])[CH:3]=1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:20]([CH2:24][C:25](O)=O)[CH:21]=[CH:22][N:23]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=2[N:1]=[C:25]1[CH2:24][N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: CCNc1cnc(C(C)=O)cc1N
Reactant: O=C(O)Cn1ccnc1-c1nccs1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)=O)ncc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone (54 mg, 0.3 mmol), (2-thiazol-2-yl-imidazol-1-yl)-acetic acid (61 mg, 0.3 mmol), EDCI (60 mg, 0.3 mmol), and pyridine (2 mL) is stirred at room temperature for 72 hr and then poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is evaporated in vacuo and the residue is taken up in acetic acid (5 mL). The mixture is heated to reflux for 16 hr and saturated NaHCO3 solution is added to neutralize the reaction. The aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is removed in vacuo and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.79 (d, 2H), 8.47 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 6.39 (s, 2H), 4.02 (q, 2H), 2.77 (s, 3H), 1.86 (t, 3H). LRMS 353.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](I)([F:12])([F:11])[F:10].OO>CS(C)=O.[Cl-].[Na+].O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[Br:8][C:5]1[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: FC(F)(F)I
Reactant: Nc1cnc(Br)cn1
Agent: [Fe+2]
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1C(F)(F)F
Temperature: 50 °C
Yield: 28.9 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (174 mg, 1 mmol) in DMSO (3 ml) stifling under Ar is added ferrocene (56 mg, 0.3 mmol) and degassed for 5 minutes with Ar. 2 ml of 1N H2SO4 in DMSO is added, followed by CF3I (0.276 ml, 3 mmol) in DMSO (2 ml), giving a slight yellow solution. 0.2 ml of 30% H2O2 is added slowly, causing the reaction to go from yellow to dark green in color. The reaction was heated to 50° C. for 2 hours under Ar. After cooling to room temperature, the reaction mixture is poured into brine, and product is extracted with EtOAc (4×20 ml). The combined organic fractions are dried with magnesium sulfate, filtered, then concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, Biotage SNAP 10 g, 0-50% EtOAc/hept) which yields 70 mg of title compound; m/z 242.0, 244.0 (M, M+2H)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:75]=[CH:74][C:65]([CH2:66][N:67]2[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:75]=[CH:74][C:65]([CH2:66][N:67]4[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CCCC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}piperidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[N:32][N:31]([CH3:35])[C:28]5=[CH:29][N:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CN(C=O)C.C(O)(=O)C>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[N:32][N:31]([CH3:35])[C:28]5=[CH:29][N:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cc5c(C)nn(C)c5cn4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4cc5c(C)nn(C)c5cn4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (5.6 mg, 0.009 mmol)and 5M NaOH (0.035 mL, 0.175 mmol) in MeOH (0.1 mL) and THF (0.5 mL) was stirred at 50° C. for 3 hours, then stored in freezer overnight. DMF (0.3 mL) and acetic acid (0.011 mL) were added and reaction mixture was concentrated to ˜0.3 mL, filtered using a syringe filter, diluted with methanol. Purified using Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) and lyophilized to give desired product. LCMS-ESI+: calc'd for C33H31ClN5O3S: 612.2 (M+H+); Found: 612.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 7.95 (s, 2H), 7.8-7.6 (m, 8H), 5.26 (s, 1H), 4.13 (s, 3H), 2.69 (s, 3H), 2.64 (s, 3H), 0.97 (s, 9H).