Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[CH2:9][CH2:10][CH2:11][CH:12]=[O:13]
Reactant: CSc1nnc(CCCCO)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nnc(CCCC=O)n1C
Yield: 35.1 %

Procedure:
To a stirred solution of 4-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-1-butanol (0.115 g) in dichloromethane (2 ml) Dess-Martin periodinane (0.24 g) was added at room temperature. After 1.5 h aqueous NaHCO3 saturated solution (2 mL) was added to the reaction mixture, the organic phase extracted with DCM (6 mL) and the solvent removed under reduced pressure to give the title compound as an oil (40 mg) that was used in the following step as a such.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Cl.ClC[C:46]1[N:50](C)[N:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:50]([CH3:46])[N:49]=[CH:48][N:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cn1ncnc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Product: Cn1ncnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and isolated as colorless gum. MS (m/e): 378.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2.[CH2:16]([OH:19])[CH2:17][OH:18].[Na]>O>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:15])[C:2]1[O:18][CH2:17][CH2:16][O:19][C:11]=1[C:10]2=[O:13]
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2cc(Cl)ccc21
Reactant: OCCO
Agent: [Na]
Solvent: O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 80 °C

Procedure:
2,3,6-Trichloronaphthoquinone (13.1 g) is added in small portions to a solution previously prepared from ethylene glycol (500 ml) and sodium metal (2.3 g) and heated to 80° C. under nitrogen. Upon completion of the addition, the reaction mixture is diluted with water (1 L) and cooled. The resulting precipitate is collected to afford 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone as an orange solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:19]=[CH:18][C:11]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br>C(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][N:15]1[CH2:16][CH2:17][C@@H:13]([O:12][C:11]2[CH:18]=[CH:19][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:14]1
Reactant: c1ccc(Cc2ccc(O[C@@H]3CCNC3)cc2)cc1
Reactant: COC(=O)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
To a solution of (R)-3-(4-Benzyl-phenoxy)-pyrrolidine (126 mg, 0.5 mmol) in anhydrous CH2Cl2 (0.5 mL) was added methyl-4-bromobutyrate (99 mg, 0.55 mmol) in CH2Cl2 (0.5 mL) and triethylamine (101 mg, 1.0 mmol. The resulting mixture was purged with nitrogen and stirred at rt for 16 h. CH2Cl2 was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with brine, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (40% EtOA /Hexane) to obtain the product as yellow solid (71 mg, 40%): MS; m/z 354.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.65-1.72 (m, 2H), 2.18-2.39 (m, 4H), 2.54-2.63 (m, 5H), 2.78-2.82 (m, 1H), 3.57 (s, 3H), 3.85 (s, 2H), 5.78 (m, 1H), 6.78 (d, 2H, J=8.8 Hz), 7.11 (d, 2H, J=8.4Hz), 7.16-7.29 (m, 5H); HPLC (ELSD); 99%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:35])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32](O)=[O:33])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].N12CCCN=C1CCCCC2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:35])=[N:14][O:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:33])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1[C@H](O)COCc1ccccc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1-{4′-[4-((S)-2-benzyloxy-1-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.232 g, 0.49 mmol) was dissolved in THF (4.6 mL) along with 4-dimethylaminopyridine (0.0065 g, 0.05 mmol) and carbonyldiimidazole (0.200 g, 1.24 mmol). After stirring at room temperature for 3.5 hours, carbonyldiimidazole (0.040 g, 0.25 mmol) was added. The reaction stirred for 1 hour then methanesulfonamide (0.117 g, 1.23 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.242 mL, 1.62 mmol) were added and the reaction was heated to 100° C. After 40 minutes the reaction was cooled and submitted to standard aqueous workup. The residue was purified on silica gel (0-100% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].I.[CH3:9][N:10]1[C:15](=[O:16])[N:14]2[CH:17]=[N:18][C:19]([C:20](SC)=[NH:21])=[C:13]2[N:12]=[N:11]1>C(#N)C>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:20]([C:19]1[N:18]=[CH:17][N:14]2[C:15](=[O:16])[N:10]([CH3:9])[N:11]=[N:12][C:13]=12)=[NH:21]
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Reactant: COC(CN)OC
Agent: I
Solvent: CC#N
Product: COC(CNC(=N)c1ncn2c(=O)n(C)nnc12)OC
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Aminoacetaldehyde dimethyl acetal (68 μL, 0.624 mmol) was added to a suspension of methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide (200 mg, 0.568 mmol) in acetonitrile (8 mL) and the mixture was stirred overnight. The precipitate, which formed during the reaction, was filtered and washed successively with water, acetonitrile, ethyl acetate and diethyl ether to give the title product as a bright yellow solid (92 mg, 58%). δH (DMSO-d6): 9.50 (3H, bs), 9.17 (1H, s), 4.69-4.71 (1H, t, J=5.3), 3.95 (3H, s), 3.70-3.72 (2H, d, J=5.3), 3.37 (6H, s).
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[H-].[Na+].C([Li])CCC.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C=O.Cl>C1COCC1.CCCCCC.O>[CH2:9]([C:4]1[C:5](=[O:6])[O:7][CH:8]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:2][C:1]=1[OH:3])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC=O
Reactant: CCCCCCC(C(C)=O)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
110.2 g of methyl 2-acetyloctanoate (the product of Example 1a) were added dropwise under argon and while stirring at 0°-5° to a suspension of 14.4 g of sodium hydride 97% in 750 ml of THF. The mixture was stirred at room temperature for 1 hour and subsequently cooled to -12°. 370 ml of 1.56M butyllithium in hexane were added within 1 hour at -12° to -10°. The mixture was stirred at -12° for 1 hour. 92.2 g of lauric aldehyde were added dropwise at -10° to the solution obtained. The mixture was stirred at this temperature for a further 1 hour. The reaction solution was added to 600 ml of water within 5 minutes while stirring. The mixture was stirred at room temperature for a further 1 hour and subsequently neutralized with 100 ml of 37% hydrochloric acid. After separating the aqueous phase the organic phase was washed with 300 ml of saturated sodium chloride solution, dried over sodium sulphate and the drying agent was filtered off under suction. After evaporation of the solvent the product was triturated with hexane. The crystallizate was filtered off under suction, washed with hexane and dried. 130.61 g (74.1%) of rac-5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one, m.p. 121.5°-122.5°, resulted.
Reaction SMILES: CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36]([OH:38])=O)[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH3:39][O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[NH2:43]>ClCCl>[CH3:39][O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:36](=[O:38])[C@@H:30]([CH2:31][C:32]([CH3:33])([CH3:34])[CH3:35])[NH:29][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
N-methylmorpholine (5 equivalents, 6.0 mmol), EDC (2.5 equivalents, 3.0 mmol) and HOBt (2.5 equivalents, 3.0 mmol) are added slowly to a solution of N-(tert-butoxycarbonyl)-3-tert-butyl-D-alanine (1.0 equivalent, 1.2 mmol) and 3-(3-pyridyl)-L-alanine methyl ester (1.0 equivalent, 1.2 mmol) in dry dichloromethane (3 ml) at −30° C. The reaction mixture slowly (approx. 12 h) warms to room temperature, with complete conversion being observed by means of HPLC (method 36). The reaction mixture is worked up by diluting with dichloromethane (20 ml) and washing with saturated sodium bicarbonate solution (10 ml). The organic phase is dried with magnesium sulphate, filtered and concentrated. The crude product is purified by flash chromatography (silica gel, gradient dichloromethane 100% to dichloromethane/methanol: 4/1), resulting in 466 mg (96% of theory) of product.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@@H:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:40]1([C:46]2[CH:53]=[CH:52][C:49](C=O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[B-]C#N.[Na+].C(O)(=O)C>>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:52][CH:53]=2)[CH:45]=[CH:44][C:43]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][N:10]4[CH2:9]3)[CH2:18][CH2:17]2)=[CH:42][CH:41]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cn2c(n1)O[C@H](CN1CCN(Cc3ccc(-c4ccccc4)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of tert-butyl (R)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 395 (101.5 mg, 0.29 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (2 ml, 14.35 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (156 mg, 0.86 mmol), sodium cyanotrihydroborate (53 mg, 0.84 mmol) and acetic acid (0.05 ml, 0.87 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (56 mg, yield 46%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:15]1OCCOCCOCCOCCOC1.[H-].[Na+].S(OC)(OC)(=O)=O.[K+].[Br-]>C(COC)OC.C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[N:4]([CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1COCCOCCOCCOCCO1
Reactant: Brc1ccccc1Nc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1ccccc1Br
Temperature: 0 °C

Procedure:
A flame-dried two-neck round bottom flask was charged with 2-bromo-N-phenylaniline (3 g, 12.2 mmol), 0.1 mL 15-crown-5, 200 mL dry THF and 50 mL dimethoxyethane under argon. The solution was cooled to 0° C. in an ice bath, 0.6 g of a 60 wt % dispersion of NaH in mineral oil (0.36 g NaH, 15 mmol) was added to the reaction mixture in small portions under argon and 1.4 mL dimethyl sulfate (1.89 g, 15 mmol) was added via syringe. After refluxing for 20 h under argon the reaction was poured carefully onto 500 g ice and extracted with Et2O (5×50 mL). The organic layers were combined, washed thoroughly with saturated sodium bicarbonate (3×25 mL), brine and water, dried over MgSO4 and the solvent evaporated under reduced pressure. The resulting oil was purified by flash column chromatography using gradient elution, starting with 100% hexanes and progressing to 30% dichloromethane in hexanes to yield 2.5 g (80%)-of a clear oil. 1H NMR (400 MHz, CHCl3) δ 3.22 (s, 3H), 6.56 (d, J=7.6 Hz, 2H), 6.75 (t, J=7.6 Hz, 1H), 7.15 (m, 3H), 7.25 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.32 (td, J=7.6 Hz, J=1.2 Hz, 1H), 7.66 (dd, J=8.0 Hz, J=1.6 Hz, 1H). 13C NMR (100 MHz, CHCl3) δ 39.1, 113.5, 117.8, 124.4, 127.9, 128.4, 129.1, 129.2, 130.6, 134.3, 147.0, 148.7. HRMS (ESI) calc for C13H12BrN [M+H]+ 262.0226, found 262.0234. IR (KBr plate) 654 (s), 691 (s), 748 (s), 872 (s), 1139 (s), 1137 (s), 1273 (s), 1346 (s), 1438 (m), 1467 (s), 1499 (s), 1580 (s), 1601 (s), 2813 (m), 2824 (s), 3058 (m), 3089 (m) cm−1.
Reaction SMILES: CN.O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:10]([O:12][C:13](=[O:27])[CH2:14][C:15](=O)[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH3:11].C([O-])(=O)C.[Na+].[C:33]([BH3-])#[N:34].[Na+]>C(O)C.C(Cl)Cl.CO.C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:27])[CH2:14][CH:15]([NH:34][CH3:33])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)Cc1c[nH]c2ccccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: CN
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CC(Cc1c[nH]c2ccccc12)NC
Temperature: 25 °C
Reaction time: 66 h

Procedure:
75 ml (680 mmol) of an approximately 30% solution of methylamine in ethanol, 132 g (1.1 mol) of magnesium sulfate monohydrate and 1.5 ml of acetic acid are added to a solution of 33.4 g (136 mmol) of 4-(1H-indol-3-yl)-3-oxo-butanoic acid ethyl ester in 350 ml of methylene chloride. The mixture is stirred at room temperature for 66 hours. The mixture is then filtered and the filter residue is washed with 1.1 liters of methylene chloride. The filtrate is concentrated by evaporation. 250 ml of methanol, 22.33 g (272 mmol) of sodium acetate, 7.8 ml (136 mmol) of acetic acid and 12.08 g (163 mmol, 85% in oil) of sodium cyanoborohydride are added to the residue (a brown oil) and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated by evaporation; 1N hydrochloric acid is added and the mixture is washed twice with diethyl ether. The diethyl ether phases are extracted three times with 1N hydrochloric acid. The combined aqueous phases are cooled and rendered basic with aqueous 50% sodium hydroxide solution. Ethyl acetate is then added. The organic phase is separated off and washed with brine, dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained in the form of a brown oil. 1H-NMR (200 MHz): 8.21 (br. s, 1H), 7.64 (d, 1H), 7.37 (d, 1H), 7.28-7.04 (m, 3H), 4.12 (q, 2H), 3.28 (m, 1H), 2.95 (d, 2H), 2.48 (m, 5H), 1.27 (t, 3H).
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:21][O:22][CH2:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH2:23][O:22][CH3:21])[CH:31]=3)[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CSc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: COCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOCCn1cc(-c2cc3c(C)nc(SC)nc3n(C3CCCC3)c2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.56 mmol), 1-(2-(methoxymethoxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (239 mg, 1.5 equiv), palladium (0) tetrakis(triphenylphosphine) (6.13 mg, 0.05 equiv.), DMF (2 mL) in a 5 mL microwave vial was added potassium carbonate (3 M, 3.0 equiv). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 30 min. at 100° C. The reaction was poured into 20 ml brine and the precipitate was collected by filtration. The title compound was obtained as a solid (208 mg, 86% yield). It was used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 19 %

Procedure:
The title compound was prepared by the procedure of Example 24, step (b) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-carbamoyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 100 mg, 0.203 mmol) and tetrabutylammonium fluoride (1.01 mL, 1.01 mmol, 1.0 M in THF). Silica gel chromatography (5% MeOH/DCM) afforded the title compound (14.1 mg, 19%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.42 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.81 (dd, 1H, J=8.6, 2.3 Hz), 7.75 (d, 1H, J=2.3 Hz), 5.81 (m, 1H), 2.28-2.40 (m, 2H), 2.04-2.17 (m, 2H), 1.63 (t, 2H, J=6.3 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C20H21N5O2, 364.2 (M+H), found 364.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.Cl.Cl[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>ClC1C=CC=CC=1>[C:15]1([N:13]2[C:12](=[O:21])[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][C:2]([N:1]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[CH:3][C:4]=4[C:5]3=[N:14]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Temperature: 175 °C
Reaction time: 60 h
Yield: 75 %

Procedure:
Equimolar quantities of 6a and bis(chloroethyl)amine hydrochloride were suspended in chlorobenzene and stirred at 175° C. for 60 hours. The solid was collected by filtration and washed with methanol, acetonitrile and diethylether in 75% yield. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.52 (4H, br), 7.12 (1H, t, J=7.47 Hz), 7.39 (3H, m), 7.45 (1H, m), 7.68 (1H, m), 8.22 (2H, dd, J=8.55, 0.98 Hz), 8.60 (1H, d, J=5.86 Hz), 9.12 (1H, br). m/z 346.4 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:2]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31].CN(C)CCCN>ClCCl.CN(C)C1C=CN=CC=1>[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:2]1)=[O:37])([O-:32])=[O:31]
Reactant: O=C(CCCc1c[nH]c2ccccc12)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CN(C)CCCN
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1cn(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12)OCc1ccccc1
Yield: 93.7 %

Procedure:
To a solution of benzyl 4-(3-indolyl)butyrate (33.70 g) in dichloromethane (400 ml) were added triethylamine (30 ml), 4-dimethylaminopyridine (1.22 g) and 3-nitrobenzoyl chloride (30.0 g). After refluxed for 16 hours, 3-nitrobenzoyl chloride (10.5 g) and triethylamine (5 ml) were added to the mixture. The mixture was allowed to reflux for 19 hours and 3-dimethylaminopropylamine (15 ml) was added at 0° C. The mixture was washed with diluted hydrochloric acid (200 ml ×2) and water (200 ml×4) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid of benzyl 4-[1-(3-nitrobenzoyl)indol-3-yl]butyrate (47.61 g).
Reaction SMILES: [CH3:1][C:2](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](O)=[O:27].C(N(CC)CC)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:35][O:34][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[C:31]=1[O:32][CH3:33])[C:26]([N:4]([CH2:3][C:2]([CH3:1])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])=[O:27]
Reactant: CC(=Cc1ccccc1)CNCCCN1CCCC1C
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCCN2CCCC2C)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 17.1 %

Procedure:
Experimental condition analogous to Example 3 were used with (2-Methyl-3-phenyl-allyl)-[3-(2-methyl-pyrrolidin-1-yl)-propyl]-amine (prepared from 2-methyl-pyrrolidine describe on scheme 10) 0.14 g (0.5 mmol), 3,4,5-trimethoxybenzoic acid 0.130 g (0.65 mmol), triethylamine 0.1 ml, and propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate) solution (50% in ethyl acetate) 0.7 g in 10 ml ethyl acetate. The free amine was transformed to the HCl salt in ether, giving 40 mg of a brown semi-solid. Yield: 15%.