Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.[C:28](OC(=N)N(C(C)C)C(C)C)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:6]([O:24][C:23]([C:5]1[N:4]2[C:26](=[O:27])[C@@H:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[C:9]([CH2:19][PH:20]([O:22][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:21])([S:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)[O:10][CH2:11][CH3:12])=[O:25])([CH3:9])([CH3:7])[CH3:5]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 21.8 g (0.05 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 500 ml of methylene chloride is added over a 30 minute interval a solution of 60.0 g (0.30 mol) of O-t-butyldiisopropylpseudourea in 100 ml of methylene chloride. The mixture is stirred at ambient temperature for 72 hours. The precipitate is removed by filtration and the filtrate is evaporated to a residue which is taken up in 200 ml of benzene and filtered again. The filtrate is extracted with three 100 ml portions of cold 1 N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC(N)=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][O:25][C:26](=[O:35])[C@@H:27]([NH:34][C:11](=[O:12])[CH:10]([C:9](=[O:23])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C(=O)NCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Yield: 66.3 %

Procedure:
A solution of N-benzyl-2-(R,S)-(4-cyano-benzyl)-malonamic acid (10 g, 32.4 mmol), (S)-amino-cyclohexyl-acetic acid methyl ester (5.94 g, 34.7 mmol), diisopropylethyl-amine (6.45 ml, 37.9 mmol), 3-hydroxy-3H-benzo[d][1,2,3]triazin-4-one (1.32 g, 8.1 mmol), and dimethylformamide (100 ml) was cooled to 10° C. A solution of dicyclohexyl-carbodiimide (7.83 g, 37.9 mmol) in toluene (10 ml) was added dropwise and the reaction mixture stand over night. The precipitated urea was sucked off, the filtrate was evaporated in vacuo, solved in ethyl acetate, washed with saturated sodium hydrogen carbonate-solution and brine, dried, and evaporated in vacuo. Crystallization from n-heptane/isopropanol gave 9.91 g (66%) of the desired product. mp.: 170-174° C., MS m/z: 462 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=2.[H+].[B-:18]([F:22])([F:21])([F:20])[F:19].[N:23]([O-])=O.[Na+]>O1CCCC1.O>[F:19][B-:18]([F:22])([F:21])[F:20].[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[N+:1]#[N:23]
Reactant: O=N[O-]
Reactant: COc1cc2ncc(N)c(Cl)c2cc1OC
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2ncc([N+]#N)c(Cl)c2cc1OC
Yield: 89 %

Procedure:
3-amino-4-chloro-6,7-dimethoxyquinoline (3.3 g) was dissolved in tetrahydrofuran (70 ml) with stirring and then cooled in an ice/water bath to below 10° C. 48% aqueous fluoboric acid (7.3 ml) was then added and the mixture stirred for 5 minutes. A solution of sodium nitrite (1.05 g) in water (2 ml) was added keeping the temperature below 10° C. The reaction mixture was then stirred for 30 minutes with cooling. The resulting yellow solid was filtered off, washed with fresh tetrahydrofuran. Carefully vac dried. To give 4-chloro-6,7-dimethoxyquinoline-3-diazonium tetrafluoroborate (4.15 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCI
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 6 h

Procedure:
A mixture of 3.47 g. of 2-chloro-5-nitrophenol, 3.74 g. of propyl iodide, 3.04 g. of anhydrous potassium carbonate and 20 ml. of acetone was refluxed with stirring for 6 hours to obtain 3.80 g of 4-chloro-3-propoxynitrobenzene having a melting point of 52° to 53° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@@H:13]1[CH2:22][OH:23]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:13]2[O:12][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1COc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 18.9 %

Procedure:
Toluene-4-sulphonyl chloride (4.2 g) was added at -10° C. under nitrogen to a stirred solution of (S)-1,4-benzodioxan-2-ylmethanol (3.3 g) in pyridine (50 ml) The mixture was allowed to warm to ambient temperature and was stirred for a further 60 hours, then poured onto ice-water (200 ml). The product was extracted into ethyl acetate (3×200 ml) then the combined extracts were washed with dilute hydrochloric acid (100 ml), and water (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. The resulting orange oil (5.84 g), which solidified slowly on standing, was purified by crystallisation from an ether and petroleum ether (b.p. 40°-60° C.) mixture to yield two batches of a white crystalline solid (2.4 and 1.2 g). The 2.4 g batch was recrystallised 3 times from ethanol, the solid obtained becoming each time less rich in the desired (R)-isomer of the product and was therefore discarded. The mother liquors from these 3 recrystallisations now contained predominantly the desired (R)-isomer of the product so they were combined, the solvent removed in vacuo and the residue recrystallised from ethanol to yield white crystals of (R)-1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate (1.2 g); m.p. 105°-107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:15][N:14]=1)=[O:12])(C)(C)C.ClC(OC)=O.C(N(CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:15][N:14]=1)=[O:12]
Reactant: Cc1cc(C(=O)NCCNC(=O)OC(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of tert-butyl[2-[[[5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]meth yl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate (90 mg, 0.160 mmol) obtained in Example 82 in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and methylene chloride and a 0.5 N aqueous sodium hydroxide were added thereto. The organic layer was separated, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (5 ml), and methyl chloroformate (19 μl, 0.240 mmol) and triethylamine (26 μl, 0.240 mmol) were added thereto. The reaction solution was stirred for 20 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 60% ethylacetate/hexane was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (71 mg, 0.136 mmol, 85%) as a white powder.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[CH2:8][CH2:7][N:6]([CH3:9])[C:5]1=O.[CH2:11]([OH:13])[CH3:12]>C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4CC(=O)[C@H]3[C@@H]2CC1)CCC(O)=O>[CH3:3][N:4]1[CH2:5][N:6]([CH3:9])[C:7](=[O:13])[CH2:8]1.[CH2:11]([OH:13])[CH3:12]
Reactant: CN1CCN(C)C1=O
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: CN1CC(=O)N(C)C1

Procedure:
In an undivided flow-through cell with ruthenized titatium anode and cathode, 1.95 g of 7-ketolithocholic acid was dissolved in an electrolyte made from 0.65 g of lithium chloride, 60 mL of 1,3-dimethyl 2-imidazolidinone and 200 mL of absolute ethanol. The solution in both the cell and the reservoir was kept under nitrogen. Initially, current of up to 4 amperes were passed through the cell but polarization occurred and the current had to be reduced to 400 ma. Electrolysis was continued until 97 coulombs had been delivered. The solvent was removed under high vacuum, and the residue dissolved in 2N sodium hydroxide. The product was precipitated by adding this alkaline solution dropwise to acidic (pH 2.0) water. The recovery was 76.9%. The percent reduction was 36.8. The ratio of ursodeoxycholic acid to chenodeoxycholic acid was 1.45.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][CH2:21][CH:22]2[O:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH:22]2[O:23][CH2:24][CH2:25][CH2:26][O:27]2)=[CH:15][CH:14]=1
Reactant: OC(CCC1OCCCO1)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC1OCCCO1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
PCC (8.16 g, 59.8 mmol) was admixed with 9 g SiO2 and ground (mortar & pestle) and suspended in Dichloromethane (360 mL). To the suspension was added in one portion Example J1, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (9 g, 29.9 mmol) dissolved in 5 mL of the same solvent. The reaction mixture was stirred for 2 hours an filtered through celite (rinse with (CH2Cl2). After being concentrated the residue was charged (CH2Cl2) to a 40 M Biotage silica gel cartridge. Gradient elution 15-70% B over 750 mL mL (A=Hexanes; B=ethyl acetate) gave Example J2, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-one 7.7 g (86%). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 4.65 (t, J=4.9 Hz, 1H), 4.09-4.06 (m, 2H), 3.74 (dt, J=11.0, 2.4 Hz, 2H), 3.06 (t, J=7.3 Hz, 2H), 2.07-2.01 (m, 3H), 1.35-1.31 (m, 1H). LCMS: RT=1.9 minutes (condition 1); C13H15BrO3 Calcd.: 299; found: 299 (M+H)+.
Reaction SMILES: [CH:1](=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].BrBr>>[CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=C1CCCC1=O
Agent: BrBr
Product: CCCCCCC1=CCCC1=O
Yield: 83.3 %

Procedure:
In a 50 ml three-neck flask fitted with a thermometer, a condenser and a stirrer were placed 2-hexylidenecyclopentanone (15 g) synthesized in Reference Example 5 and bromine (0.03 g), followed by 6 hours of the reaction at 100-120° C. The crude product was purified by column chromatography (hexane/ethyl acetate: 95/5) to obtain 12.5 g of 2-hexyl-2-cyclopentenone (GC purity: 98.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2CCC3(CC2)OCCO3)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: O=C1CCC(c2cccc(F)c2)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
The compound (18) (61.9 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 47.2 g of 4-(3-fluorophenyl)cyclohexanone (19). The yield based on the compound (18) was 93.7%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:25])(=[O:18])=[O:19]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 64 hours. The compound was purified by two silica gel chromatographies on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (30%). MS (ESI): m/z=449.11 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:19])=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC2CC2)c(F)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluorobenzoic acid (1.57 g) in THF (50 mL) were added oxalyl dichloride (0.982 mL) and DMF (2 drops), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give 4-(cyclopropylmethoxy)-3-fluorobenzoyl chloride. This compound was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6]([NH:10]C(=O)OC(C)(C)C)[CH:5]=[C:4]([Cl:18])[N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6]([NH2:10])[CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: CNc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1c(N)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 2,6-dichloro-3-(methylamino)pyridin-4-ylcarbamate 2.44 (0.60 g) was dissolved in a mixture of DCM/TFA 1:1 (5 mL) and stirred at room temperature. After 1 h, LC/MS indicated full conversion to desired product. Mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed with 1N HCl and layers separated. Aqueous layer was extracted again with ethyl acetate and saturated NaHCO3 (aq), and layers separated. Organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield 2,6-dichloro-N3-methylpyridine-3,4-diamine 2.45 that was used for next step without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H7C12N3: 192.0; found: 192.1.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11](Br)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[S:1]1[C:5]([C:6]2[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2cc3ccccc3s2)n1
Temperature: 140 °C
Yield: 16.9 %

Procedure:
A 5 mL Personal Chemistry microwave tube was charged with 1-(2-(4-(benzo[b]thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (103 mg, 0.22 mmol), phenyl boronic acid (55 mg, 0.44 mmol), a 2 M aqueous solution of sodium carbonate (0.22 mL, 0.44 mmol), dioxane (2 mL) and tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.044 mmol). The vessel was sealed and heated to 140° C. for 20 min with stirring. After cooling to r.t. the mixture was diluted with ethyl acetate (10 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (chloroform/methanol 99:1 to 96:4 followed by a second column: ethyl acetate/hexane/methanol 50:48:2) to afford the title compound (17 mg, 17%). 1H NMR: δ (CDCl3, 400 MHz) 1.47 (s, 6 H), 3.60-3.68 (m, 2 H), 3.81-3.92 (m, 2 H), 6.32 (br. s., 1 H), 6.92 (s, 1 H), 7.26 (t, J=7 Hz, 1 H), 7.32 (t, J=7 Hz, 1 H), 7.36 (dd, J=3 Hz, 2 H), 7.44-7.47 (m, 3 H), 7.50 (d, J=8 Hz, 1 H), 7.79 (d, J=8 Hz, 1 H), 8.22 (s, 1 H): HRMS (M+H)+ Calcd. C25H23N5O2S 458.1650, found 458.1616
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:6]=2)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nn(CCN3CCCCC3)cc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (1.00 g, 6.14 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then 1-(2-chloro-ethyl)-piperidine hydrochloride (1.73 g, 9.40 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, the mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.37 (m, 2 H) 1.45 (m, 4 H) 2.42 (m, 4 H) 2.85 (t, J=6.44 Hz, 2 H) 4.66 (t, J=6.61 Hz, 2 H) 7.49 (m, 1 H) 8.19 (m, 2 H) 8.91 (s, 1 H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][N:27]=[C:26]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][P:42]([O:45][CH2:46][CH3:47])([OH:44])=[O:43])=[CH:37][C:36]=4[O:48][CH3:49])[N:25]=3)=[C:19]([C:50](=[O:53])[NH:51][CH3:52])[N:18]=2)[CH:14]=[C:13]1[C:54]([O:56][CH3:57])=[O:55])C1C=CC=CC=1.C>CCO.[Pd]>[CH2:46]([O:45][P:42]([CH2:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:26]2[N:25]=[C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([C:15]4[CH:14]=[C:13]([C:54]([O:56][CH3:57])=[O:55])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH:16]=4)=[N:18][C:19]=3[C:50](=[O:53])[NH:51][CH3:52])[C:29]([C:30]([F:32])([F:33])[F:31])=[CH:28][N:27]=2)=[C:36]([O:48][CH3:49])[CH:37]=1)([OH:44])=[O:43])[CH3:47]
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cc(C(=O)OC)n(CCCOCc5ccccc5)c4)nc3C(=O)NC)n2)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cc(C(=O)OC)n(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 1-[3-(benzyloxy)propyl]-4-[5-({2-[(4-{[ethoxy(hydroxy)phosphoryl]methyl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-6-(methylcarbamoyl)pyridin-2-yl]-1H-pyrrole-2-carboxylate (Compound 38B, 582 mg, 0.717 mmol) and Palladium 10% wt. on Calcium Carbonate:Carbon black (63.4 mg, 0.031 mmol) in EtOH (11.4 mL), was evacuated and purged with d with H2(g) (3×) and left to stir overnight at rt for 16 hrs. The reaction mixture was filtered and concentrated in vacuo to a 330 mg of a solid which was used without further purification (64%). 1H NMR (400 MHz, CD3OD) δ 8.88-9.02 (m, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.72 (d, J=6.3 Hz, 1H), 7.56-7.62 (m, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.09 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 4.47 (t, J=6.8 Hz, 2H), 3.85-3.92 (m, 5H), 3.85 (br. s., 3H), 3.54-3.61 (m, 2H), 3.03 (d, J=22.0 Hz, 2H), 2.95-2.99 (m, 3H), 1.97-2.06 (m, 2H), 1.17 (t, J=7.1 Hz, 3H). MS (ESI): m/z=722.60 [M+H]+. UPLC: tR=1.22 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2ncoc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncoc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methylbenzoxazol-6-yl)-2-pyridylamine (44) (26.6 mg, 0.12 mmol) in 2 ml DCM was added 2-fluorobenzoyl chloride (29 μl, 0.24 mmol) followed by addition of DIEA (105 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (180 μl) at r.t. for 40 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 24.1 mg N-[5-(5-methylbenzoxazol-6-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (45) as off-white solid. (yield: 57.8%, purity>95%).