Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].[I:12]Cl.S([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.O>[I:12][C:10]1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:7][O:8][C:9]=1[CH3:11]
Reactant: ClI
Reactant: Cc1cc(OCC(C)C)no1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1onc(OCC(C)C)c1I
Temperature: 80 °C
Reaction time: 14 h
Yield: 68.4 %

Procedure:
To a stirred solution of 3-isobutoxy-5-methyl-isoxazole (570 mg, 3.67 mmol) in AcOH (15 mL) and water (18 mL) at ambient temperature was added ICl (716 mg, 4.40 mmol) and the reaction mixture heated at 80° C. After 2 h the reaction mixture was cooled to room temperature. After 14 h, a solution of sodium sulfite (Na2SO3, 1 g) in water (15 mL) was added and the reaction mixture extracted into ethyl acetate (2×50 mL). The combined extracts were washed with water (3×30 ml) and brine then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, 0-10% ethyl acetate in heptane) gave the title compound (706 mg, 68%) as a colourless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH:19](B1OB(C=C)OB(C=C)O1)=[CH2:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([CH:19]=[CH2:20])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: C=CB1OB(C=C)OB(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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 90 °C
Yield: 16.5 %

Procedure:
To a solution of 4-chloro-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.5 g, 1.821 mmol) in dioxane (8 mL) and water (2 mL) were added trivinylboroxin (0.588 g, 3.64 mmol), cesium carbonate (1.780 g, 5.46 mmol). The reaction mixture was flushed with nitrogen for 10 min and Tetrakis (0.210 g, 0.182 mmol) was added. The reaction mixture was heated at 90° C. for 2 h then filtered through a pad of celite and washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 15% ethyl acetate in hexane to give N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine as a white solid (0.08 g, 12.21% yield). LCMS: R.T.=1.14 min; [M+H]+=267.1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer is charged with 30 g of 2-chloroacetophenone and 36.3 g of potassium phthalimide in 120 ml of DMF. After 4 h at RT, the mixture is concentrated under vacuum. The solid obtained is taken up in 120 ml of DCM and 100 ml of 1 sodium hydroxide solution. The organic phase is washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under vacuum. The solid obtained is triturated in diisopropyl ether. The insolubles are filtered off and dried under vacuum to give 42.6 g of 2-(2-oxo-2-phenylethyl)-1H-isoindole-1,3(2H)-dione in the form of a beige solid, which is used as it is in the following step.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[C:12]([O:16][C:17](=[O:20])[CH2:18]Br)([CH3:15])([CH3:14])[CH3:13].Cl>C(O)C>[C:12]([O:16][C:17]([CH2:18][S:8][C:5]([CH3:7])([CH3:6])[C@H:4]([NH:3][C:17]([O:16][CH2:12][CH3:13])=[O:20])[C:9]([OH:11])=[O:10])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (0.81 g; 35.2 mmol) was added in portions to 40 mL ethanol while cooling. Subsequently D-penicillamine (2.50 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which bromoacetic acid tert.-butyl ester (2.55 mL) was added. The mixture was allowed to stir 16 h at ambient temperature and subsequently hydrolyzed with 2 N HCl. The solvents were distilled off, the residue was redissolved in 50 mL of water and 50 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (2.1 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 10) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a colorless oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 0.86 g (15%) of the title compound as a colorless oil. (+)-APCI-MS: 358 (MNa+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16]OC(OCC)=O)[C@H:13]([OH:23])[CH2:12][N:11]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:31]([CH3:34])([O-:33])=[O:32]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][CH2:34][N+:31]([O-:33])=[O:32])[C@H:13]([OH:23])[CH2:12][N:11]1[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)OCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(CC[N+](=O)[O-])=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-((ethoxycarbonyloxy)methyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 218, 14.5 g, 32.54 mmol) was taken up in nitromethane (100 ml, 1854.52 mmol) and degassed for 5 minutes. Pd2(dba)3 (1.49 g, 1.63 mmol) was added and the reaction mixture was stirred under nitrogen at room temperature for 18 hrs. Reaction mixture was dried directly onto silica and purified by flash chromatography using 0-50% EtOAc/Hexanes. The title compound was obtained as a yellow oil (6 g, 44.3%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:23][CH:22]=[N:21][N:20]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:23][CH:22]=[N:21][N:20]=3)[CH:14]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nnc[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2nnc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 43, 220 mg, 0.65 mmol) in tetrahydrofuran (5 ml) at room temperature was added lithium aluminium hydride (1.3 ml, 1.30 mmol, 1.0M in THF) dropwise over a few minutes. The mixture was then heated under reflux for 2 hours and then cooled to 0° C. 2N sodium hydroxide (1.0 ml) was added cautiously followed by ethyl acetate (10 ml) and the mixture was stirred rapidly for 30 minutes, then filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by silica column chromatography eluting with ethyl acetate:methanol:amnonia solution (0.880) (80:20:1) to afford the title compound (190 mg, 90%) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O1CCOCC1.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([N:23]=[N+:24]=[N-:25])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 98 %

Procedure:
At from 23° to 30° C add a warm solution of 7.5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 200 ml of acetone and 250 ml of dioxane dropwise to a solution of 1.84 g of sodium azide in 24 ml of water. Stir the resulting reaction mixture for a further 15 minutes and then dilute it with 600 ml of water cooling with ice to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid azide [m.p. 134° C (with decomposition)].
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCOc1ccc(C(=O)O)nn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 1 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.54 g, 60% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 9.24 min (99.01%); mp: 126-128° C.; 1H NMR (DMSO-d6) δ 1.41 (t, J=7.1 Hz, 3H, CH3), 1.88 (s, 3H, CHH), 1.97-2.13 (m, 1H, CHH), 2.52-2.62 (m, 2H, CHH, CHH), 2.61-2.78 (m, 1H, CHH), 4.58 (q, J=7.1 Hz, 2H, CH2), 4.65 (d, J=6.2 Hz, 2H, CH2), 7.35 (d, J=9.1 Hz, 1H, Ar), 7.81 (s, 3H, Ar), 8.08 (d, J=9.1 Hz, 1H, Ar), 9.84 (t, J=6.3 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 21.00, 28.57, 29.09, 42.38, 58.75, 63.47, 117.91, 121.75, 123.16, 128.80, 129.65, 131.37, 133.53, 147.14, 149.10, 162.90, 165.86, 167.73, 167.88, 172.14, 172.19; LCMS: MH=452; Anal Calcd for C22H21N5O6+0.25H2O: C, 57.96; H, 4.75; N, 15.36. Found: C, 57.66; H, 4.61; N, 15.14.
Reaction SMILES: C(N(CC)C(=O)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][CH2:15][OH:16])C.[OH-].[Na+]>C(O)C>[Cl:12][C:8]1[C:7]([CH2:13][CH2:14][CH2:15][OH:16])=[C:6]([OH:5])[CH:11]=[CH:10][CH:9]=1
Reactant: CCN(CC)C(=O)Oc1cccc(Cl)c1CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCCc1c(O)cccc1Cl
Yield: 213.6 %

Procedure:
To a solution of the 3-chloro-2-(3-hydroxypropyl)phenyl diethylcarbamate (0.410 g; 1.43 mmol) in ethanol (14.5 ml) was added solid sodium hydroxide (0.144 g; 3.59 mmol) and the reaction mixture was heated at reflux for 21 h. After cooling, the volatiles were removed under reduced pressure, water was added and the mixture was extracted with diethyl ether, the combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-100%) in heptane furnished 0.57 g (79%) of the desired 3-chloro-2-(3-hydroxypropyl)phenol.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH:13]1([CH3:23])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15](O)[CH2:14]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][C@H:15]1[C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18][C@@H:13]([CH3:23])[CH2:14]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 70 h
Yield: 13 %

Procedure:
A solution of 11.36 g (50.0 mmol) 2-acetylbenzoic acid, 4.88 g (40.0 mmol) DMAP and 23.40 g (150.0 mmol) (−)-menthol in 80 ml dichloromethane was cooled in an ice bath before adding a solution of 11.36 g (55.0 mmol) DCC in 40 ml dichloromethane for 15 min. The reaction mixture was maintained with stirring at 40° for 70 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) then with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4), concentrated, chromatographed (SiO2, toluene) and recrystallised in hexane to give 1.96 g (13%) (1R, 3R, 4S)-3-p-menthanyl 2-acetylbenzoate in the form of white crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:25][C:26]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34](Cl)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.O>CN(C=O)C>[Cl:25][C:26]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.2 %

Procedure:
Triethylamine (12.5 mL, 0.0889 mol) and 1-(N-Boc-aminomethyl)-3-(aminomethyl)benzene (17.71 g, 74.94 mmol) were sequentially added to a solution of 2,4-dichloro-3-nitroquinoline (18.2 g, 0.0750 mol) in DMF (90 mL), and the reaction was stirred at room temperature under nitrogen for 1.5 hours. The reaction was poured into water (2 L), and the suspension was stirred for 15 minutes. Most of the water was decanted away from the resulting precipitate, which was dissolved in ethyl acetate (600 mL). The ethyl acetate was separated from a small amount of remaining water and then removed under reduced pressure. The resulting solid was dried under vacuum to provide 38.24 g of tert-butyl 3-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a sticky, amber solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCSCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[S-:35].[Na+]>>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4][C@@H:3]([CH2:2][S:35][C:27]2[N:26]([CH3:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)[O:8]1
Reactant: Cn1c([S-])nc2ccccc21
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: [Na+]
Product: Cn1c(SC[C@@H]2C[C@H](CC(=O)OC(C)(C)Cc3ccccc3)OC(C)(C)O2)nc2ccccc21

Procedure:
The procedure was carried out in the same manner as in Example 11, except that 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof, and sodium 1-methyl-1H-benzo[d]imidazole-2-thiolate (3.7 g) prepared in Example 9 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate. The title compound was obtained (4.7 g).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][N:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][N:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1nccn2c(-c3ccc(NC(=O)OC(C)(C)C)cc3)nnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nccn2c(-c3ccc(N)cc3)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of methyl 3-(4-(tert-butoxycarbonylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate (61D) (130 mg, 0.35 mmol) in CH2Cl2 (1 mL) was added TFA (1 L). The resulting mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The obtained residue was stripped with CH2Cl2 and dried in high vacuum to yield the title compound as brown oil (94 mg). HPLC/MS (Method D): retention time=0.39 min, [M+H]+=270.5.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:17]=[C:18]([N+:22]([O-])=O)[CH:19]=[CH:20][CH:21]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc(N)c1
Yield: 99.9 %

Procedure:
A suspension of 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)nitrobenzene (0.4 g) in ethanol (10 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 150 mg) under a hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)aniline (365 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(N(CC)CC)C.O1CCCC1>O.CN(C)C=O>[CH:33]1([C:36]([NH:1][C:2]2[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][N:3]=2)=[O:37])[CH2:35][CH2:34]1
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1NC(=O)C1CC1
Yield: 56.2 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-3-pyridyl]-2-propenoate (200 mg), cyclopropanecarbonyl chloride (58 mg), triethylamine (0.1 m), tetrahydrofuran (4 ml) and dimethylformamide (1 ml) were stirred at room temperature for 20 minutes. A small amount of water was added dropwise and the precipitated solid was filtered out to obtain 130 mg of a faint yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([OH:41])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([NH:30][C:24]([CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]3[N:17]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:13]4[N:29]=[CH:28][S:27][C:14]=4[N:15]=3)[CH2:19]2)=[O:25])=[CH:32][C:33]=1[OH:41]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.5 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (80 mg, 0.19 mmol) and methyl 4-amino-2-hydroxybenzoate (32 mg, 0.19 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (63 mg, 0.76 mmol) and EDCI (147 mg, 0.76 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, methanol (5 mL) was added, the precipitate was collected by filtration to afford methyl4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-hydroxybenzoate (110 mg, crude) which was used directly in the next step without further purification. LC-MS: tR=565 [M+H]+, 1.64 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]([C:15]4[CH:16]=[C:17]([OH:26])[CH:18]=[CH:19][C:20]=4[N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:40][CH3:41].O>CN(C=O)C.C(#N)C>[C:27]([N:12]1[C:11]2[CH:31]=[CH:32][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:14]=[C:13]1[C:15]1[CH:16]=[C:17]([O:26][CH2:40][CH3:41])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CCI
Reactant: CC(C)(C)n1c(-c2cc(O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a stirred solution of 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-phenol (50 mg, 0.12 mmol) in DMF (3 mL) is added potassium carbonate (24 mg, 0.18 mmol) followed by iodoethane (9.4 ul, 0.12 mmol). The resulting mixture is stirred at room temperature for 3 hours and then is warmed to 65° C. for 4 hours. The reaction is cooled to room temperature, poured into water and the product extracted into EtOAc (2×). The combined organics are dried (MgSO4), filtered, and concentrated. The remaining residue is purified by silica gel flash column chromatography (12 g silica gel, 2-8% MeOH/DCM). Product-containing fractions are combined and concentrated to give a solid which is diluted with acetonitrile. The white solid is collected via filtration and washed with acetonitrile to afford the title compound (20 mg, 38%). LCMS (ESMS): m/z 455.74 (M++1)