Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCO[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O
Agent: Cl
Product: N[C@@]1(C(=O)O)CCO[C@@H]1CCCB(O)O
Temperature: 25 °C

Procedure:
A solution of (2R,3S)-3-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydrofuran-3-carboxamide (860 mg) in 6 N HCl (15 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separator funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous solution was concentrated. Purification by RP-HPLC (10-100% acetonitrile in water) gave (2R,3S)-3-amino-2-(3-boronopropyl)tetrahydrofuran-3-carboxylic acid, as a white solid (269 mg). 1H NMR (D2O, 300 MHz) δ 3.97 (m, 2 H), 3.82 (m, 1 H), 2.66 (ddd, J1=15 Hz, J2=9.5 Hz, J3=5.5 Hz, 1 H), 2.14 (ddd, J1=15 Hz, J2=9 Hz, J3=6.5 Hz, 1 H), 1.22-1.49 (m, 4 H), 0.67 (m, 2 H); MS (+CI): m/z for C8H16BlNO5: expected 217.1; found 435.3 (2M+H)+, 417.2 (2M+H−H2O)+, 217.7 (M+H)+, 200.0 (M+H−2H2O)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1.[Cl:27]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[C:5]([Cl:27])=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1cccc(CNC(=O)c2cc(-c3ccc(C)o3)nc(N)n2)n1
Solvent: CC(=O)O
Product: COCc1cccc(CNC(=O)c2nc(N)nc(-c3ccc(C)o3)c2Cl)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of 2-amino-N-(6-methoxymethyl-2-pyridylmethyl)-6-(5-methyl-2-furyl)pyrimidine-4-carboxamide (50 mg, 0.142 mmol) in acetic acid (10 mL) at room temperature was treated with N-chlorosuccinimide (24 mg, 0.156 mmol), stirred at 100° C. for 2 h, cooled to room temperature, concentrated in vacuo and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid was triturated with diethyl ether and filtered to give the title compound (30 mg, 54%) as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1C)[CH:7]=[O:8])[CH3:2].[OH:13][C:14]1C=C(C=C(O)[CH:21]=1)C=O.C(I)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:11]=1)[CH:7]=[O:8])[CH3:21]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B21, vide infra) by reaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF using K2CO3 as base.
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:13](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:14]([OH:16])=[O:15])=[O:9])([O-:3])=[O:2].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)=[C:13](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[C:14]([O:16][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:15])=[O:9])([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 300 mg of (2Z)-4-({[2,3-bis(nitrooxy)propoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 5 mL of DMF was added 69 μL benzyl bromide followed by 81 mg of potassium carbonate (325 mesh). The resulting mixture was stirred at rt for 30 min. The reaction was then quenched with saturated solution of NH4Cl and extracted with Et2O/hexanes (½, 2 times). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a pale yellow residue. Flash chromatography of the crude material over silica gel (10-70% EtOAc/hexane) afforded 250 mg of the title compound as a white solid. 1H NMR (500 μL, acetone-d6): δ 7.80 (d, 2H), 7.48 (d, 2H), 7.42-7.35 (m, 5H), 7.21-7.18 (m, 3H), 7.13-7.10 (m, 2H), 5.77-5.73 (m, 1H), 5.36 (s, 2H), 5.33 (s, 2H), 5.04 (dd, 1H), 4.84 (dd, 1H), 4.64 (dd, 1H), 4.48 (dd, 1H), 3.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:16][O:15][C:13]([CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:12]1[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate (2.27 g, 10.2 mmol) and triethylamine (2.13 ml, 15.3 mmol) in dichloromethane (60 ml) was added at 0° C. toluene-4-sulfonyl chloride (2.32 g, 12.2 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (50 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from diethyl ether/hexane to give the title compound, off-white solid, m.p. 91° C. and MS: m/e=378.3 (M+H+).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1cccnc1S
Reactant: BrC1CCCC1
Product: O=C(O)c1cccnc1SC1CCCC1

Procedure:
2-Mercapto-nicotinic acid (1.0 g, 6.44 mmol) and bromo-cyclopentane (2 mL, 19.33 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH:15](OCC)OCC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[Cl:12][C:11]1[C:2]2[N:3]([CH:14]=[CH:15][N:1]=2)[C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc2ccccc2n2ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 218.2 %

Procedure:
To a stirred suspension of 2-amino-3-chloroquinoxaline (25.5 g, 141.8 mmol) in water/THF 1:1 (500 mL), at rt was added 2-bromo-1,1-diethoxyethane (83.8 g, 425.4 mmol) in one portion. After stirring at rt for 1 h, the mixture was heated to reflux for 3 h under stirring and then stirred for an additional 15 h at rt. The pH value of the mixture was adjusted to pH 8 by addition of solid sodium carbonate and the mixture was subsequently extracted with ethyl acetate (3×500 mL) and the combined organic extracts were dried with sodium sulfate. Removal of the solvent yields 4-chloro-imidazo[1,2-a]quinoxaline as an orange-white solid (63 g, 93%): 1H-NMR (300 MHz, d6-DMS): δ=9.05 (d, 1H), 8.51 (dd, 1H), 8.1 (dd, 1H), 7.99 (d, 1H), 7.89 (td, 1H), 7.76 (td, 1H) ppm. UPLC-MS: RT=0.88 min; m/z 204.6 [MH+]; required MW=203.6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1Cl
Temperature: 120 °C
Yield: 47.8 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (50.0 mg, 0.159 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (45 mg, 0.19 mmol), 10-camphorsulfonic acid (5.0 mg, 0.022 mmol) and isopropyl alcohol (2 mL) and heated at 120° C. for 30 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and extracted into EtOAc. The organic layer was washed with NaHCO3 and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue purified by chromatography (silica gel, 5% NH4OH in MeOH gradient with DCM). The appropriate fractions were combined and evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (39.0 mg, 48%) as a white powder that had the following properties: m.p.=146-147° C., bubbled, remelt at 184-187° C.; LC/MS (ESI+): 513 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.90 (s, 1H), 8.10 (s, 1H), 7.4-7.2 (m, 5H), 7.10 (d, J=8.5, 1H), 7.0 (s, 1H), 6.2, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1COCC1>[C:17]([O:3][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C=C/C(=O)O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Yield: 75.1 %

Procedure:
Sodium hydride (1.40 g, 58 mmol) was added portionwise to a solution of (E)-3-(3-hydroxy-4-methoxy-phenyl)-acrylic acid (5.15 g, 26.5 mmol) in THF (100 mL) at 0° C. The resulting mixture was allowed to reach the RT, and acetic anhydride (4 mL, 42.4 mmol) was added. After stirring at reflux temperature for 6 hrs, the reaction mixture was concentrated under reduced pressure. The residue was taken up with AcOEt, and washed with water, aqueous sodium hydrogencarbonate, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was triturated with AcOEt. After filtration and drying, 4.7 g of the title (E)-3-(3-acetoxy-4-methoxy-phenyl)-acrylic acid were obtained, as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI>O>[CH3:3][N:24]([C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)c1ccncc1)c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Sodium hydride (60% (w/w) oil mixture) (200 mg, 0.500 mmol) was added at 0° C. to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 5 N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (121 mg, 0.496 mmol), obtained as described in Referential example 1-3. The resulting mixture was stirred for one hour, and an N,N-dimethylformamide (DMF) solution of methyl iodide (0.8 M, 0.62 ml, 0.496 mmol) was added thereto at 0° C. The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g, hexane/ethyl acetate=1/1). Thus, N-methyl-N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0614) (65.9 mg, 51.5%) was yielded as a colorless solid.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH:6]1([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH2:8][CH2:7]1.Cl>CCOCC.O1CCCC1>[CH3:12][C:11]([OH:13])([CH2:10][CH2:9][CH:6]1[CH2:8][CH2:7]1)[CH2:4][C:3]#[CH:2]
Reactant: CC(=O)CCC1CC1
Reactant: C#CCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC(C)(O)CCC1CC1
Temperature: 25 °C

Procedure:
To 1 part by volume of magnesium in 25 parts by volume of tetrahydrofuran under argon is added a small amount of propargyl bromide and mercuric chloride to initiate reaction. Once the reaction is started 6.3 parts of propargyl bromide and 36 parts of 4-cyclopropyl-2-butanone in 50 parts by volume of tetrahydrofuran is added dropwise so as to maintain reflux. Upon completion of the reaction, the reaction mixture is cooled to room temperature and poured into a mixture of ether and 1N HCl. The aqueous layer is extracted twice with ether. The ether extracts are combined and washed 3 times with water and one time with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to provide a residual oil. The residual oil is distilled under high vacuum to provide 4-methyl-4-hydroxy-6-cyclopropyl-hex-1-yne.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[NH:4][C:5]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)[CH:8]=[CH:7][N:6]=1.[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH2:37])=[CH:32]2)=[O:27].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH:37][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[NH:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:23])=[O:22])[CH:10]=1)=[CH:32]2)=[O:27]
Reactant: COC(=O)c1c2ccc(N)cc2nn1C
Reactant: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1c2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N(C)C)c3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid (112 mg, 0.35 mmol), 6-amino-2-methyl-2H-indazole-3-carboxylic acid methyl ester (62 mg, 0.3 mmol), N-methylmorpholine (0.09 mL, 0.82 mmol) and HATU (152 mg, 0.4 mmol) were suspended in dry DMF (3 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane. The organic phase was washed consecutively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1) to give 6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (53 mg, 35%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.30 (1H, s), 8.79 (1H, s), 8.30 (1H, m), 8.15 (1H, d), 7.92-7.99 (2H, m), 7.82 (1H, s), 7.75 (1H, dd), 7.62 (1H, dd), 7.25-7.29 (1H, m), 6.93-6.96 (1H, m), 6.68 (1H, t), 6.55 (1H, d), 4.45 (2H, d), 4.41 (3H, s), 3.99 (3H, s), 2.92 (6H, s); m/z (ES+) 502 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][NH2:27].O1CCCC1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH3:26])=[O:6]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1F
Yield: 54 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and 2M methylamine-tetrahydrofuran solution instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([OH:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:70][CH:71]=[CH2:72].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([O:61][CH2:72][CH:71]=[CH2:70])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexane is added 1.5 equivalents of allyl trichloroacetimidate, and the reagents are allowed to mix for 5 minutes. A catalytic amount of trifluoromethanesulfonic acid is then added slowly via syringe and the mixture is stirred at room temperature. After 3 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][C:26]#[N:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][C:26]#[N:27])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: N#CCBr
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC#N)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and bromo-acetonitrile (0.022 mL). MS (m/e)=405.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: CNc1nccc(-c2cccnc2Sc2ccc(N)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNc1nccc(-c2cccnc2S(=O)c2ccc(N)cc2)n1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a cold (0° C.) suspension of 4-(2-(4-aminophenylthio)pyridin-3-yl)-N-methylpyrimidin-2-amine (400 mg, 1.28 mmol) in 20 mL of dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (330 mg, 1.28 mmol, 77% maximum purity) in dichloromethane. The reaction was stirred for 7 hours at 0° C. Then the reaction flask was stored in the freezer overnight without stirring. After 17 hours, the reaction was removed from the freezer and was stirred for another 6 hours in an ice-water bath. The solid was filtered off and collected. The product, 4-(2-(4-aminophenylsulfinyl)pyridin-3-yl)-N-methylpyrimidin-2-amine was obtained as an off-white solid. 1H NMR (Varian, 300 MHz, CDCl3): 8.76 (s, 1H), 8.35 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.60 (m, 1H), 7.46 (m, 3H), 6.78 (d, J=4.9 Hz, 1H), 6.46 (d, J=8.0 Hz, 2H), 5.63 (br s, 2H), 2.81 (s, 3H).
Reaction SMILES: [F:1][C:2]([P:8](C(F)(F)C(F)(F)F)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[OH-].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:26]>COCCOC.O>[P:8]([Cl:26])([C:9]([C:10]([F:13])([F:12])[F:11])([F:15])[F:14])[C:2]([C:3]([F:6])([F:5])[F:4])([F:7])[F:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (3.0 mmol) of tris(pentafluoroethyl)phosphine, (C2F5)3P, in 1,2-dimethoxyethane is treated with an excess (6 mmol) of a 1.5 M solution of KOH in water. The mixture is stirred at room temperature for 30 min, and the solvent is removed in vacuo. The residue is taken up in 1,2-dimethoxyethane, and an excess of PCl5 (6 mmol) is added, giving bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, identified as described above.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(C)c1
Product: Cc1cccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)c1

Procedure:
The title compound, yellow solid, MS: m/e=290.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-methylbenzene.