Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C@H:10]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]2[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)Cl.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH:14]=[O:15])[C@@H:11]([O:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C@H:10]([O:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[C@H:9]2[O:26][Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](CO)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](C=O)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a suspension of ((2R,3R,4S,5R,6S)-6-(4-chloro-3-(phenoxymethyl)phenyl)-6-methoxy-3,4, 5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol (23.0 g, 36.7 mmol) in DMSO (250 mL) was added DCM (20 mL) to make a clear solution. The solution was cooled to 0° C. followed by addition of triethyl amine (122.4 ml, 881.0 mmol) and sulphur trioxide pyridine complex (87.5 g, 550.6 mmol). The reaction mixture was stirred at 0 to 10° C. for 3 h under nitrogen atmosphere. After completion of the reaction as confirmed by TLC, the crude compound was extracted with diethyl ether (1 L). The organic layer was separated, washed with water (2×500 mL), dried over Na2SO4, concentrated in vacuo to afford crude title compound (22.9 g, 100%) as a viscous oil which was used for next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nn1cccc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nn1cccc1

Procedure:
In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-aminopyrrole to produce 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 11.39 (s, 1H), 8.35 (d, 1H, J=3.5 Hz), 6.83 (t, 2H, J=2.3 Hz), 6.07 (t, 2H, J=2.3 Hz). LCMS: ret. time: 18.95 min.; purity: 97%; MS (m/e): 213 (MH+).
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=1>CN(C=O)C>[CH2:1]([O:5][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=1)[C:2]#[C:3][CH3:4]
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2F)cn(C)c1=O
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(C)(=O)=O)cc1-c1cc(C)c(=O)n(C)c1
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of but-2-yn-1-ol (191 mg, 2.72 mmol) in anhydrous DMF (3 mL) was added NaH (109 mg, 2.72 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at this temperature for 1 hr. The title compound from Step 1 (200 mg, 0.68 mmol) was added and the reaction mixture was stirred at 0° C. for 2 hrs. After this time, it was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give a crude product that was purified by prep-HPLC to give the title compound (56.01 mg, 23.9%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.46 (s, 2H), 7.24 (d, J=8.8 Hz, 1H), 4.79 (d, J=2.0 Hz, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.22 (s, 3H), 1.87 (s, 3H). LCMS: 346.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH:16]3[CH2:18][CH:13]1[CH2:14][N:15]3[CH:19]([CH3:21])[CH3:20])=[N:7][N:6]=[CH:5]2.[CH:22]1([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:22]1([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH:16]5[CH2:18][CH:13]3[CH2:14][N:15]5[CH:19]([CH3:21])[CH3:20])=[N:7][N:6]=[CH:5]4)[CH:28]=2)[CH2:23][CH2:24]1
Reactant: CC(C)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CC4CC3CN4C(C)C)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A mixture of 2-(6-bromophthalazin-1-yl)-5-isopropyl-2,5-diaza-bicyclo[2.2.1]heptane (60 mg, 173 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (52 mg, 173 μmol) and tetrakis(triphenylphosphine)palladium (10 mg, 9 μmol)in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (0.5 mL, 1 mmol) at 22° C. under nitrogen. The mixture was heated up to 90° C. and stirred for 1 h. The reaction was monitored by MS. After about 1 h at 90° C., MS showed all starting material was converted to product (M+1=442). The mixture was cooled down to room temperature (22° C.). The mixture was transferred directly to silica gel and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOHIDCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (60 mg). Found MS (ES+): 442(M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:9][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:30][CH:31]=1)[CH3:2]
Reactant: CCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
Into a solution of methyl 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.59 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.6 ml), and the resulting mixture was stirred at 65° C. for 24 hours. Into this reaction mixture was added further a 1 M aqueous solution of potassium carbonate (1.3 ml), and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (215 mg) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH:22]([CH3:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH:22]([CH3:28])[C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cnc(Br)cn2)cc1
Reactant: CC(Br)C(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2cnc(Br)cn2C(C)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of N-(5-bromopyrazin-2-yl)-4-methylbenzenesulfonamide (1.73 g) in DMF (20 ml) was added NaH (60% in oil, 0.316 g) at 0° C., and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromo-1-cyclopropylpropan-1-one (1.87 g) at room temperature, and the mixture was stirred overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.02 g) as a solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=O.[CH:7](=[O:10])[CH2:8][CH3:9].C(OC(=O)C)(=O)C>C1CCCCC1.N(CC(O)=O)C>[CH:7](/[C:8](/[CH3:9])=[CH:2]\[C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: CCC=O
Reactant: COC(=O)C=O
Agent: CNCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)/C=C(/C)C=O
Yield: 68.9 %

Procedure:
18 g (0.2 mol) of sarcosine were suspended by stirring in 500 ml of cyclohexane in a flask and, starting at 20° C., a mixture of 1809 g (20.6 mol) of methyl glyoxylate and 1194 g (20.6 mol) of propionaldehyde was added within 90 min. During the dropwise addition the temperature rose slowly to the boiling point (75° C.). After the addition was complete, initially a small amount of water was removed as azeotrope, and then the mixture was distilled until the bottom temperature was 100° C. to remove cyclohexane. Then 2220 g (21.8 mol) of acetic anhydride were added to the residue, and the reaction mixture was distilled to a bottom temperature of 150° C. to remove acetic acid. Fractional distillation of the bottom product yielded 1822 g (14.2 mol) of methyl 3-formylcrotonate, corresponding to a yield of 69% of theory, with a trans/cis isomer ratio of 93/7.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([O:36][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([OH:36])[CH2:10]1
Reactant: CC(C)(O)CCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 91.7 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7-diene (700 mg), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (20 ml), followed by reaction for 6 hours. After adding ethyl acetate, the reaction mixture was washed with saturated brine, a saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the resulting residue was purified by column chromatography (dichloromethane: methanol=9:1) to give the titled compound (0.41 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19]CC)=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 80.7 %

Procedure:
30 mg of the compound (198) obtained in Example 69 was added to 0.4 ml of acetic acid and 0.1 ml of 12N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, water was added to the reaction solution, and deposited solids were filtered off and washed with water, ethanol and ether in this order to obtain 22 mg of the subject compound (199) in a 81% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.Cl.[C:38]([O:42][C:43](=[O:46])[CH2:44][NH2:45])([CH3:41])([CH3:40])[CH3:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.ON1C2C=CC=CC=2N=N1>[C:38]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1)=[O:24])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzotriazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s), 4.17 (2H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a suspension of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (166 mg, 0.400 mmol) in tetrahydrofuran (5 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.270 mL, 0.810 mmol) at 0° C., and the mixture was stirred at 0° C. for 15 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (170 mg, 0.381 mmol, 95%).
Reaction SMILES: [CH2:1]([O:15][C:16](=[O:39])[CH2:17][CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CC)=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.C(OC(=O)CCSCCC(OCCCCCCCCCCCCCCCCCC)=O)CCCCCCCCCCCCCCCCC.[P].P(O)(O)O.P(O)(O)O.P(O)(O)O.C(C(CCCCCCCCCCCCC)C(CCCCCCCCCCCCC)(C1C=C(C(C)(C)C)C(O)=CC=1C)C(CCCCCCCCCCCCC)(CCCCCCCCCCCCC)C(CCCCCCCCCCCCC)(C1C=C(C(C)(C)C)C(O)=CC=1C)C1C=C(C(C)(C)C)C(O)=CC=1C)CCCCCCCCCCCC>>[CH2:1]([O:15][C:16](=[O:39])[CH2:17][CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCC(CCCCCCCCCCCCC)C(CCCCCCCCCCCCC)(c1cc(C(C)(C)C)c(O)cc1C)C(CCCCCCCCCCCCC)(CCCCCCCCCCCCC)C(CCCCCCCCCCCCC)(c1cc(C(C)(C)C)c(O)cc1C)c1cc(C(C)(C)C)c(O)cc1C
Agent: CCCCCCCCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC
Agent: OP(O)O
Product: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC

Procedure:
dimyristyl-3,3'-thiodipropionate (molecular weight, 571; melting point 47 to 54° C.; commercial name, DMTD "YOSHITOMI" (YOSHITOMI), SUMILIZER TPM (SUMITOMO), ANTIOX M (NICHI-YU)). distearyl-3,3'-thiodipropionate (molecular weight, 683; melting point 61 to 68° C.; commercial name, DSTP "YOSHITOMI" (YOSHITOMI), SUMILIZER TPS (SUMITOMO), ANTIOX S (NICHI-YU)). pentaerythritol-tetrakis-(β-lauryl-thiopropionate) (molecular weight, 1162; melting point >46° C.; commercial name, SEENOX 412S (CYPRO), MARK AO-412S (ADECA ARGUS), SUMILIZER TP-D (SUMITOMO)). bis[2-methyl-4{3-n-alkylthio propionyloxy}-5-tert-butylphenyl]sulfide (molecular weight, 874 to 927; commercial name, MARK AO-23 (ADECA ARGUS). phosphorus acide [1,1-biphenyl-4,4'-zyl-bis tetrakis [2,4- bis(1,1-dimethylethyl)phenyl]ester (molecular weight, 1035; melting point 75 to 95° C.; commercial name, SANDSTAB P-EPQ (SAND), IRGAFOS P-EPQ FF (CIBA-GEIGY)). 3,5-di-tert-butyl-4-hydroxy benzyl phosphite di-ethylester (molecular weight, 356; melting point 117 to 122° C.; commercial name, IRGANOX 1222 (CIBA-GEIGY)). tris (mixed mono-di-nonylphenyl-phosphite (molecular weight, 815; commercial name, MARK 329K (ADECA ARGUS), WESTON 399 (BORGWARNER)). tetra tridecyl 4,4'-butylidene bis-(3-methyl-6-t-butylphenol)-di-phosphite (molecular weight, 1238; commercial name, MARK 260 (ADECA ARGUS)). hexa tridecyl 1,1,3-tris(2-methyl-4-hydroxy-5-t-butylphenyl)butane triphosphite (molecular weight, 1828; commercial name, MARK 522A (ADECA ARGUS)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH2:16].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH:16][C:24](=[O:26])[CH3:25]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 85.7 %

Procedure:
To a solution of trans-1-[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (95.0 mg, 0.433 mmol) and triethylamine (72.4 μL, 0.520 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (45.1 μL, 0.477 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (97 mg, yield 86%).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=1
Reactant: [NH4+]
Reactant: COc1ccccc1-c1nsc(S)n1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1nsc(SN)n1
Reaction time: 0.17 h

Procedure:
A solution of 4.6 g of 5-mercapto-3-(2-methoxyphenyl)-1,2,4-thiadiazole in 70 ml of 5% sodium hydroxide and a solution prepared by diluting 44 ml of 5.25% NaOCl to 70 ml with water were added dropwise simultaneously to 190 ml of ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 3.0 g of solid, m.p. 136°-138° C. dec.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:43][C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([CH2:51][NH:52][CH2:53][CH3:54])[C:45]=2[F:55])[CH:42]=1)[C:38]#[N:39].[NH:56]1[CH:60]=[C:59]([C:61]([OH:63])=O)[N:58]=[CH:57]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CN(C=O)C>[Cl:50][C:49]1[CH:48]=[CH:47][C:46]([CH2:51][N:52]([CH2:53][CH3:54])[C:61]([C:59]2[N:58]=[CH:57][NH:56][CH:60]=2)=[O:63])=[C:45]([F:55])[C:44]=1[O:43][C:41]1[CH:40]=[C:37]([C:38]#[N:39])[CH:36]=[C:35]([Cl:34])[CH:42]=1
Reactant: CCNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C(O)c1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.6 %

Procedure:
DMF (3 mL) and DIPEA (0.1 mL, 0.59 mmol) were added to a mixture of HATU (0.12 g, 0.32 mmol), 3-chloro-5-({6-chloro-3-[(ethylamino)methyl]-2-fluorophenyl}oxy)benzonitrile (0.10 g, 0.29 mmol) and 1H-imidazole-4-carboxylic acid (0.05 g, 0.41 mmol). The yellow solution was stirred at RT under a nitrogen atmosphere for 48 h then ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was washed with saturated NaHCO3 solution (2×100 ml), brine (150 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA) to give the title compound (0.046 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.80 (m, 1H), 7.89-8.03 (m, 1H), 7.82 (s, 1H), 7.44-7.56 (m, 3H), 7.33 (t, 1H), 4.69-5.18 (m, 2H), 3.33-3.79 (m, 2H), 1.01-1.27 (m, 3H). LCMS m/z 431.2 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16](C(O)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[O:29][CH3:30])[CH:3]=1.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[N:66]([CH:68]=[O:69])C>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:68]([NH2:66])=[O:69])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[O:29][CH3:30])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.21 g 4-[4-Fluoro-2-((1R,2R)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 5 ml ammonia 0.5 M in dioxane, 0.22 g HATU, 0.10 ml DIPEA and 2 ml DMF was stirred at rt overnight. The reaction mixture was diluted with water and filtered. The solid was dried in vacuo at 65° C.