Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:34])([F:33])[C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([C:30](O)=[O:31])[N:21]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[N:9]=1.N1C=CC=CC=1.[NH2:41][C:42]1[C:51]([CH3:52])=[CH:50][C:49]([Cl:53])=[CH:48][C:43]=1[C:44](NC)=[O:45]>C(#N)C>[F:34][C:7]([F:6])([F:33])[C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([C:30]3[O:31][C:44](=[O:45])[C:43]4[CH:48]=[C:49]([Cl:53])[CH:50]=[C:51]([CH3:52])[C:42]=4[N:41]=3)[N:21]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[N:9]=1
Reactant: O=C(O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cn4nc(C(F)(F)F)cc4C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon 0.12 ml (1.60 mmol) of methanesulphonyl chloride in 3 ml of acetonitrile are cooled to 0° C. and subsequently a solution of 540 mg (1.228 mmol) of 5-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid in 0.17 ml (2.09 mmol) of pyridine and 6 ml of acetonitrile is added dropwise. The mixture is stirred at this temperature for 15 minutes and then a solution of 228 mg (1.228 mmol) of 2-amino-5-chloro-3,N-dimethylbenzamide in 0.35 ml (4.30 mmol) of pyridine and 6 ml of acetonitrile is added. After a further 15 minutes at 0° C. the mixture is admixed with 0.12 ml (1.60 mmol) of methanesulphonyl chloride and warmed slowly to room temperature overnight. The solvent is removed in vacuo, 15 ml of water are added and the crystals formed are filtered off with suction.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(OCC)(=O)C>[N+:1]([C:4]1[O:8][C:7]([C:9]([Cl:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.2 g of 5-nitrofuran-2-carboxylic acid in 15 ml of ethyl acetate, was added 2.5 g of phosphorous pentachloride. The resulting mixture was stirred for 45 minutes at room temperature. Distilling off the solvent gave the oily substance, 5-nitrofuran-2-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.CO.O.[OH-].[Na+:40]>C1COCC1>[Na+:40].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([O-:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)O)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)[O-])c4)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Suspend 2.52 g (5.39 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid in a mixture of 10 ml of THF, 10 ml of methanol and 1 ml of water at RT, add 5.39 ml of 1N sodium hydroxide solution dropwise and stir the resulting solution at RT for 10 min, before filtering off with suction through a fine frit (removal of suspended particles). Concentrate the solution under reduced pressure and treat the residue with ethanol. Filter off the insoluble solid with suction, wash with a little ethanol and dry under reduced pressure, then under high vacuum. Concentrate the filtrate, stir the residue again with a little ethanol and thus obtain a second product batch after filtering off with suction. After combining the two fractions, a total of 2.32 g (87.9% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][O-:22].[Na+]>CO>[Cl:8][C:6]1[N:7]=[C:2]([O:22][CH3:21])[C:3](=[O:20])[N:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)nc(Cl)cn1-c1ccnn1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cn(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 3,5-dichloro-1-(1-phenyl-1H-pyrazol-5-yl)pyrazin-2(1H)-one (0.627 g) in methanol (15.0 mL) was added sodium methoxide (0.132 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was concentrated and adjusted to pH 5-6 with 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.362 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (57 mg, 0.2 mmol), 4-trifluoromethyl-benzoic acid (42 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give the title compound (65 mg, 71%) as a brown solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.73-1.76 (m, 2H), 1.87-1.92 (m, 2H), 2.85-2.90 (m, 2H), 3.29-3.32 (m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, 3H), 4.32 (t, J=4.80 Hz, 2H), 6.32 (d, J=2.02 Hz, 1H), 7.26 (d, J=8.59 Hz, 1H), 7.50 (d, J=1.78 Hz, 1H), 7.75 (d, J=2.53 Hz, 1H), 7.88-7.94 (m, 3H), 8.15 (d, J=8.84 Hz, 2H), 9.81 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2, found 459.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C:16]([CH3:23])([CH3:22])[CH2:15]1.O1CCOCC1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:22][C:16]1([CH3:23])[CH2:15][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20]
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 19.3 %

Procedure:
5-Bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (144 mg, 0.36 mmol) was placed in a microwave vial and dissolved with 1,4-dioxane (6 mL) and water (3 mL). 3-Thiopheneboronic acid (92 mg, 0.72 mmol) and K2CO3 (150 mg, 1.1 mmol) were added. Argon was bubbled in the mixture for 10 min with stirring. PdCl2(dppf) (21 mg, 0.29 mmol) was added, and argon was bubbled another 10 min. The vial is sealed and heated in a microwave for 5 min at 100° C. on high absorption. The reaction was evaporated to remove most of the dioxane. The residue was partitioned between ethyl acetate and water. The layers were separated, the organic layer was dried (MgSO4), and the solvent was removed under vacuum. The residue was dissolved in DMSO (3 mL), and was purified on a Gilson HPLC. The desired fractions were concentrated, giving 28 mg (19%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15].[H-].[Na+]>O1CCOCC1>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:15][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(N)cn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in dioxane (30 mL) at room temperature was added 2-(dimethylamino)ethanol (309 mg, 3.5 mmol) and 60 wt. % NaH (0.15 g, 3.7 mmol) and the reaction mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The reaction mixture was poured onto ice-cold water and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (340 mg, 61%) as a purple solid: ESI MS m/z 182 [C9H15N3O+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][N:3]=1.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:9]1([CH2:8][N:7]([C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)[C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nnc(NCc2ccccc2)s1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nnc(N(Cc2ccccc2)C(=O)Cc2ccccc2)s1

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-benzylamine (15 g, 0.073 mole) in pyridine (200 ml) was refluxed with phenylacetyl chloride for 6 hours. The pyridine was removed under educed pressure and the residue treated with water and extracted with ether. The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ethanol to give the title compound, m.p. 128° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@@H:4]([NH:6][C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[C:3]1([CH3:20])[CH3:19].[NH2:21][CH2:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][C:33]([F:36])([F:35])[F:34])[CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([CH2:23][CH2:22][NH:21][C:9]2[N:8]=[C:7]([NH:6][C@@H:4]3[CH2:5][C@H:2]([OH:1])[C:3]3([CH3:20])[CH3:19])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:25][C:26]=1[O:32][C:33]([F:34])([F:35])[F:36])#[N:29]
Reactant: N#Cc1ccc(CCN)cc1OC(F)(F)F
Reactant: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)[C@@H](O)C[C@H]1Nc1nc(NCCc2ccc(C#N)c(OC(F)(F)F)c2)ncc1C#N
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
A mixture of 4-(((1R,3S)-3-hydroxy-2,2-dimethylcyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, 0.27 mmol), 4-(2-aminoethyl)-2-(trifluoromethoxy)benzonitrile (60 mg, crude)) and DIEA (105 mg, 0.81 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (34.4 mg, 0.077 mmol, 40% yield, over two steps). 1H NMR (400 MHz, CD3OD) δ8.14-8.07 (m, 1H), 7.82-7.80 (m, 1H), 7.45-7.43 (m, 2H), 3.97-3.93 (m, 1H), 3.83-3.70 (m, 2H), 3.68-3.59 (m, 1H), 3.10-2.01 (m, 2H), 2.58-2.54 (m, 1H), 2.15-2.06 (m, 1H), 1.21 (s, 3H), 0.95 (s, 3H). MS (ESI) m/z 447.2 [M+1]+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:36])[NH:6][C@H:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9])(C)[CH3:2].C(OC(N[C@H](C1CCCCC1)C(N1CCC[C@H]1C(O)=O)=O)=O)C>>[CH2:1]([O:4][C:5](=[O:36])[NH:6][C@H:7]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Agent: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C1CCCCC1
Yield: 124.9 %

Procedure:
Using the procedure described in example 91d 0.350 g of 1-[(R)-ethoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid was converted into 0.430 g (83%) of the title compound. (+)-APCI-MS: 482 (MH+).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH3:20])=[C:11]2[CH3:21])=[O:7])[CH3:4]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH2:20][Br:1])=[C:11]2[CH3:21])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(CBr)n2C(C)=O
Yield: 44.9 %

Procedure:
Bromine (0.40 g) was added dropwise over 1 minute to a stirred solution of 1-acetyl-2,3-dimethylindole-5-carboxylic acid ethyl ester (0.65 g) in acetic acid (1.3 ml). After a few minutes a solid precipitated. The mixture was diluted with ca 5 ml. of ether and the solid was filtered off, washed with ether and dried to give 1-acetyl-2-bromomethyl-3-methylindole-5-carboxylic acid ethyl ester (0.38 g), m.p. 125°-130° . The product was unstable and was used directly in the next stage.
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH2+:13][CH2:14][CH:15]=2)[O:4]1.C(N(C(C)C)C(C)C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([N:13]1[CH2:12][CH:11]=[C:10]([B:5]2[O:4][C:3]([CH3:16])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]2)[CH2:15][CH2:14]1)(=[O:29])=[O:28]
Reactant: CC1(C)OB(C2=CC[NH2+]CC2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR=0.98 min; Mass spectrum (ESI+): m/z=288 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: CNC
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (5.0 g, 21.2 mmol) in 100 mL of methanol at 0° C. was added dimethylamine (5.3 mL of a 40% aqueous solution). The resulting reaction mixture was stirred at 0° C. for 10 min, during which time the product crashed out as white needles. The mixture was diluted with water and filtered, washing once with water. The needles were collected and dried in vacuo to provide 2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (4.4 g, 85%), mp 72-74° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-])=O)(=[O:23])=[O:22])[CH2:17][C@@H:16]2[CH3:33])=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].CC(O)=O.CCO>CCOC(C)=O.[Pd]>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:34])[F:35])[C:4]([F:7])([F:6])[F:5])=[CH:10][N:11]=2)[C@@H:16]([CH3:33])[CH2:17]1)(=[O:22])=[O:23]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2N)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
Using a new 10% Pd/C CatCart cartridge (30 mm), a H-Cube/Gilson (Thalesnano Technology, Budapest, Hungary) system was purged with 1:1 0.5 M AcOH in EtOAc:EtOH. The CatCart was pre-saturated with H2 for 10 min (using the pre-saturate setting in the autosampler software program) at 0.5 mL/min. A solution of ((S)-1,1,1,3,3,3-hexafluoro-2-(2-(2-methyl-4-(2-nitrophenylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-2-propanol (0.21 g, 0.40 mmol) in 4.0 mL 1:1 0.5 M AcOH in EtOAc:EtOH was prepared. Three injections set at 1.5 mL were made, 30 mm 10% Pd/C CatCart, flow rate 0.5 mL/min, “1 bar” i.e., setting at “Full H2” on H-cube; temp 40° C.; 10 mL volume collected for each injection. The collected solution was concentrated and then dissolved in CH2Cl2. The solution was treated with saturated aqueous sodium bicarbonate then passed through a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) dried (Na2SO4), and then concentrated. The residue was then purification by silica gel chromatography (0 to 70% EtOAc/hexane) to afford (S)-2-(2-(4-(2-aminophenylsulfonyl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (92 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.53 (s, 2H), 7.40 (dd, J=1.4, 8.2 Hz, 1H), 7.25-7.34 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.63 (t, J=7.1 Hz, 1H), 6.06 (s, 2H), 4.94 (br s, 1H), 4.57 (d, J=13.7 Hz, 1H), 3.75 (d, J=11.5 Hz, 1H), 3.51 (d, J=11.9 Hz, 1H), 3.10-3.27 (m, 1H), 2.60 (dd, J=3.7, 11.9 Hz, 1H), 2.38-2.47 (m, 1H), 1.10-1.22 (m, 3H). m/z (ESI, +ve ion) 499.9 (M+H)+. GK-GKRP IC50 (Binding)=0.508 μM; GK-GKRP EC50 (LC MS/MS-2)=0.516 μM.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:13][CH2:12]2)([OH:10])[CH3:9])=[N:6][CH:7]=1.[CH:24]1([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]3[CH:39]=[C:38](B4OC(C)(C)C(C)(C)O4)[CH:37]=[C:36]([CH3:49])[CH:35]=3)[N:28]=2)[CH2:26][CH2:25]1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH:24]1([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]3[CH:39]=[C:38]([C:2]4[CH:3]=[CH:4][C:5]([C:8]([C@H:11]5[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:13][CH2:12]5)([OH:10])[CH3:9])=[N:6][CH:7]=4)[CH:37]=[C:36]([CH3:49])[CH:35]=3)[N:28]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Cl)cn2)CC1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(-c3cc(C)cc(Nc4nccc(C5CC5)n4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of trans-butyl 4-(1-(5-chloropyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate (110 mg, 0.324 mmol), 4-cyclopropyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (114 mg, 0.324 mmol), BrettPhos Precatalyst (13.0 mg, 0.016 mmol), BrettPhos (18.0 mg, 0.034 mmol) and sodium carbonate (330 μl, 0.660 mmol) in dioxane (1618 μl) was heated to 100° C. for 2 hours. The reaction mixture was cooled to room temperature and TFA (0.5 mL) was added. The reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA (45-80%). The major peak was collected and lyophilized to give trans-butyl 4-(1-(5-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)pyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate as a colorless solid. MS ESI calc'd for C32H41N4O3 [M+H]+ 529. found 529.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:17].CCN(C1C=CC=CC=1)CC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1Cl
Yield: 77136.7 %

Procedure:
A mixture of 4-hydroxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (50 g, 0.234 mmol), POCl3 (110 mL, 1.17 mmol) and diethylaniline (70 mL, 0.28 mmol) was refluxed for 5 h. The solvent was removed under vacuum and the residue was dissolved in ice H2O and cautiously neutralized with aqueous NaHCO3. After extraction with EtOAc (3×400 mL), the organic extracts were combined, dried and concentrated to give 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (42 g, 77% yield). 1H NMR (300 MHz, CDCl3): δ 8.92 (s, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][P:3]([O-:6])[O:4][CH3:5].C(N(CC)CC)C.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15]>CN(C)C=O.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>[CH3:1][O:2][P:3]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([C:14](=[O:16])[CH3:15])[N:18]=[CH:19]2)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: CC(=O)n1ncc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1ccc2c(cnn2C(C)=O)c1
Temperature: 105 °C
Yield: 55.2 %

Procedure:
291 μl (1.09 eq; 3.172 mmol) of dimethylphosphite, 442 μl (1.09 eq; 3.172 mmol) of triethylamine and 134 mg (0.04 eq; 0.116 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 897 mg (1 eq; 2.91 mmol) of trifluoromethanesulfonic acid 1-acetyl-1H-indazol-5-yl ester in solution in 60 ml of dimethylformamide. The medium is heated at 105° C. for 4 hours under an argon atmosphere. The solvent is evaporated off under reduced pressure in a rotary evaporator, with 40 ml of toluene being added. The reaction crude is taken up in 40 ml of ethyl acetate and then washed with 50 ml of water. The organic phase is dried over magnesium sulfate and then filtered and the solvent is evaporated off under reduced pressure in a rotary evaporator. 973.6 mg of crude product are obtained. The reaction crude is purified by flash chromatography (silica 35-70 μm), eluent: ethyl acetate/cyclohexane 80:20 to obtain 430.5 mg of (1-acetyl-1H-indazol-5-yl)phosphonic acid dimethyl ester.