Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][NH2:39])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][NH:39][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(CCN)ccc1OCc1cccc2ccccc12
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1

Procedure:
13.9 g of (2S,3S)-2-(tert-butoxycarbonyl-amino)-3-methyl-valeric acid (BOC-L-isoleucine) and 18.5 g of 2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethylamine are stirred at room temperature for two hours together with 25 g of (benzotriazol-1-yl)-tris(dimethylamino)-phosphonium hexafluorophosphate and 155 ml of diisopropylethylamine in 300 ml of dimethylformamide. The reaction mixture is then introduced into 800 ml of water. Extraction is carried out twice using 800 ml of ethyl acetate each time. The organic phases are washed twice using 250 ml of 2N hydrochloric acid each time, twice using 250 ml of 2N potassium hydrogen carbonate solution each time and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (2S,3S)-2-(tert-butoxy-carbonyl-amino)-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide in the form of a yellowish oil, which can be purified by chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])[CH3:16].O>C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: CC(C)c1cccc(N)c1
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
A solution of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.75 g, 3.62 mmol) and 3-isopropylaniline (0.82 mL, 5.79 mmol) in ethanol (11 mL) was heated to 80° C. for 10 hours. The reaction was cooled to 0° C., water was added and the mixture was stirred for 15 minutes. The product was filtered, washed with water and dried in the vacuum oven to provide pure 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile (0.88 g, 80%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.1 Hz, 6 H) 2.9 (dq, J=6.9 Hz, 1 H) 7.2 (m, 3 H) 7.4 (t, J=7.8 Hz, 1 H) 8.2 (s, 1 H) 8.6 (s, 1 H) 9.1 (s, 1 H) 10.1 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1.C1(C)C=CC=CC=1.[CH3:34][O-:35].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([O:35][CH3:34])[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:25])[CH3:26])[N:3]=1
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(N)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (380 mg, 1.06 mmol) was azeotroped with toluene (2×12 mL). The residue was dissolved in 5 mL of DMF as a clear yellow solution, to which was added NaOMe (2.30 mL of a stock solution with concentration of 0.52 mmol/mL, 1.19 mmol, 1.12 equiv) at room temperature in one portion. The resulting mixture was stirred at room temperature for 18 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (276 mg) as a light yellow oily residue. LC-MS (ES) m/z=372 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][CH:11]([C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]>C1COCC1>[CH3:10][CH:11]([C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: CCC(C)c1ccc(OCc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 117 mg) in THF (dry) (4 mL) was added 2-chloroethanesulfonyl chloride (0.185 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-{[4-(1-methylpropyl)phenoxy]methyl}pyridin-2-amine (150 mg) in THF (dry) (4 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and crystallized from THF/IPE to give the title compound (34.9 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(NS(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1.2 g, 4.15 mmol) was dissolved in tetrahydrofuran (20 mL). To the solution was added triethylamine (0.64 mL, 4.57 mmol). To the mixture was added dropwise methanesulfonyl chloride (0.39 mL, 4.95 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into ice-water (20 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the titled compound (1.43 g) as colorless powdery crystals.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1)[CH3:2].N1C=CC=CC=1CO>>[CH3:2][C:1]1[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:6][O:7][C:3]=1[CH3:4]
Reactant: CCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Agent: OCc1ccccn1
Product: Cc1onc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)c1C

Procedure:
The title-compound was prepared from 6-chloro-3-(4,5-dimethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine prepared in Example 32 part a and 2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 2.30 (3H, s, Me), 2.49 (3H, s, Me), 5.73 (2H, s, CH2O), 7.29 (1H, m, Ar—H), 7.70-7.83 (3H, m, 3 of Ar—H), 7.96 (1H, m, Ar—H), 8.31 (1H, d, J=8.3 Hz, Ar—H, 8.64-8.70 (2H, m, 2 of Ar—H); MS (ES+) m/e 373 [MH]+; Anal. Found C, 64.38; H, 4.05; N,22.60. C20H16N6O2 requires C, 64.50; H, 4.33; N, 22.57%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.Cl>O1CCOCC1>[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(Cc2ccc(CC(=O)O)cc2)CC1
Yield: 52.7 %

Procedure:
Using 2.2 g of methyl 4-bromomethylphenylacetate, 1.9 g of 1-(2-tolyl)piperazine hydrochloride, 2.5 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from ethanol-ether to provide 1.7 g of the title compound melting at 249° C.-252° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:36]2[CH:35]=[C:34]([F:37])[CH:33]=[CH:32][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: Cc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-methyl-5-fluorobenzene boronic acid (73 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc×3. The combined extracts were dried and evaporated. The residue was purified on a 12+M column eluting with Pet Et2O to 60% EtOAc/Pet Et2O to afford the title compound in a 27% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][CH2:7][C:8]32[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]3)=[CH:4][CH:3]=1>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][CH2:7][C:8]32[CH2:12][CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3ccc(Cl)cc32)C1
Solvent: CCOCC
Product: Cl
Product: Clc1ccc2c(c1)C1(CCNC1)CC2
Reaction time: 8 h
Yield: 181.1 %

Procedure:
To a solution of tert-butyl 6-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]-1′-carboxylate (Prep42, 2.50 g, 8.14 mmol) in ether (50 ml), a 1N solution of hydrochloric acid-ether (50 ml) was added and stirred overnight. The mixture was washed by anhydrous ether. The residue was dissolved in DCM and concentrated to give the title compound (1.8 g, y=81.3%).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:19]=2)=[O:15])[NH:5]1.[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37](O)=[O:38])[C:33](=[O:40])[NH:32]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37]([N:27]2[CH2:26][CH2:25][N:24]([C:20]3[CH:19]=[C:18]([CH2:17][NH:16][C:14]([C:6]4[NH:5][C:4](=[O:3])[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:15])[CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:28]2)=[O:38])[C:33](=[O:40])[NH:32]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: O=C(NCc1cccc(N2CCNCC2)c1)c1nc2ccccc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(CC(=O)N2CCN(c3cccc(CNC(=O)c4nc5ccccc5c(=O)[nH]4)c3)CC2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of 4-oxo-N-[(3-piperazin-1-ylphenyl)methyl]-3,4-dihydroquinazoline-2-carboxamide dihydrochloride obtained in Reference Example 116 (0.109 g, 0.250 mmol), (2,5-dioxoimidazolidin-4-yl)acetic acid (0.047 g, 0.300 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole (0.068 g, 0.500 mmol) in DMF (5 mL) was stirred at room temperature for 1 hr. Triethylamine (0.139 mL, 1.00 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from methanol-diethyl ether to give the title compound as a pale-yellow powder (0.078 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.125 g, 0.449 mmol) was reacted with N-(2-azidoethyl)-4-heptylbenzamide (0.129 g, 0.449 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-heptylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), δ 7.65 (d, 2H), δ 7.27 (s, 1H), δ 7.09 (d, 2H), δ 6.39 (s, 1H), δ 6.22 (s, 2H), δ 4.47 (s, 2H), δ 3.81 (s, 2H), δ 3.96 (s, 4H), δ 2.20 (s, 2H), δ 2.05 (s, 2H), 1.48 (m, 12H), δ 1.17 (m, 8H), δ 0.77 (t, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 149.6, 148.2, 147.1, 138.6, 131.5, 128.6, 127.4, 122.1, 106.4, 84.8, 67.1, 49.4, 40.2, 37.9, 36.9, 31.9, 31.3, 31.1, 29.8, 28.4, 29.3, 28.9, 28.3, 28.1, 28.0, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for C31H47N7O3 (M+) 565.3704. found 656.3737, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-heptylbenzamide hydrochloride (0.194 g, 86% yield). 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), δ 7.71 (d, 2H), δ 7.24 (d, 2H), δ 6.45 (s, 1H), δ 4.74 (s, 2H), 3.90 (s, 2H), δ 2.63 (s, 2H), δ 2.61 (t, 2H), δ 2.41 (S, 2H), δ 1.58 (m, 6H), δ 1.26 (m, 10H), δ 0.85 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 150.2, 147.4, 131.2, 128.5, 127.6, 127.3, 108.4, 51.4, 39.6, 36.5, 35.6, 31.8, 331.3, 29.1, 29.1, 28.3, 28.0, 27.7, 24.1, 22.6, 13.4, 13.3 ppm; HRMS (ESI) calcd for C26H39N7O (M+) 465.3216. found 465.3207.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:40][S:41]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:43])=[O:42]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)c(Cc3cccc4ccccc34)sc21
Reaction time: 8 h

Procedure:
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 4) (403 mg) was dissolved in dichloromethane (6 ml). Triethylamine (300 μl) was added followed by methanesulfonyl chloride (150 μl) and the mixture was stirred overnight. Sodium bicarbonate (aqueous) was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried, filtered and evaporated to give the subtitle compound (0.57 g).
Reaction SMILES: [Si]([O:8][C@H:9]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=1)[CH2:10][NH:11][C@H:12]([CH3:34])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:23])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.CO.O.ClCCl>CO>[NH3:11].[CH2:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:33][CH:25]1[NH:24][C:22](=[O:23])[CH2:21][CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=2)[CH3:34])[CH:15]=1
Reactant: C[C@H](Cc1cccc(CCC(=O)NC2Cc3ccccc3C2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Cc1cccc(CCC(=O)NC2Cc3ccccc3C2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N

Procedure:
Prepared from 3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,3-dihydro-1H-inden-2-yl)propanamide (Preparation 49) according to the method for example 1 using methanol:water (2.4:1 v/v) instead of acetic acid as solvent and using dichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the column eluent to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)[CH2:10][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Yield: 100 %

Procedure:
Dissolved the product from Example 39F (300 mg, 0.502 mmol) in ethanol (5 mL) and THF (5 mL) then added platinum(IV) oxide (22.8 mg, 0.1 mmol) and a hydrogen balloon and stirred the solution at room temperature for 2.5 h. Solution was filtered through celite and washed with methanol (10 mL), then concentrated to give the title compound (285 mg, 100%) as a colorless semi-solid and a 1/1 mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1.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>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(Cl)nc1Cl
Reactant: Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2.89 mmol (500 mg) of 2,6-dichloronicotinonitrile and 3.18 mmol (551 mg, 1.1 eq.) of 4-aminophenylboronic acid are dissolved under an inert atmosphere in 33.3 ml of dioxane. 680 mg (8.09 mmol, 2.8 eq.) of sodium bicarbonate and then 8.3 ml of water are subsequently added. The mixture is stirred for 5 minutes under an inert atmosphere and then 334 mg (0.29 mmol, 0.1 eq.) of tetrakis(triphenylphosphine)palladium are added. The reaction mixture is brought to reflux (100° C.) for 2 hours and is then cooled to ambient temperature. The reaction medium is filtered and then extracted four times with ethyl acetate. The organic phases are combined, washed twice with a saturated aqueous sodium chloride solution, dried with magnesium sulphate, and concentrated. A yellow solid is then obtained. This crude is purified on a column of 90 g of silica, with an eluent gradient of 20% to 50% of ethyl acetate in heptane. The expected product is obtained in the form of a yellow solid (531 mg).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C(F)=CC=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][CH:32]=[CH:31][C:30]=3[F:34])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1cccc(F)c1CCl
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3c(F)cccc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(F)c1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 18.7 %

Procedure:
The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[C:6]2[CH2:10]O)[CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:10][C:6]1[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1CC1CC1
Product: Cl
Product: ClCc1nccn1CC1CC1
Temperature: 90 °C

Procedure:
To 1-cyclopropylmethyl-2-hydroxymethylimidazole (2.50 g) was added thionyl chloride (25 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature, the solvent was distilled off under reduced pressure and the obtained solid was washed with ethyl acetate, to give 2-chloromethyl-1-cyclopropylmethylimidazole hydrochloride. (2.96 g) as brown crystals.