Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[CH:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([NH:26][C:27]([C:29]3[C:38]([OH:39])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])[C:19]2=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[C:25]1([NH:26][C:27]([C:29]2[C:38]([O:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:28])[C:19]2[C:20](=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1cccc2ccccc12)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3cc4ccccc4cc3C(=O)Nc3cccc4ccccc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), naphthol AS-BO (626 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (43 mg, yield 17%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([NH2:40])(=[O:39])[CH2:36][CH2:37][CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[C:35]([NH:40][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(Br)c1
Reactant: CCCC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)ccn1
Yield: 44.5 %

Procedure:
100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 25 hours to a bath temperature of 90° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel first with hexane, then with hexane:ethyl acetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide with a melting point of 173° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[C:22]1=[O:29].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:23]2[CH2:24][CH2:25][N:21]([CH3:20])[C:22]2=[O:29])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CN1CCC(C(=O)O)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(=O)Nc2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)C1=O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.5179 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (148.3 mg, 1.04 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (297.8 mg, 1.55 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (209.9 mg, 1.55 mmol), N-ethyl-N-isopropylpropan-2-amine (334.7 mg, 2.59 mmol) and THF (25 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 80.4%). LRMS (APCI pos) m/e 512 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.42 (d, 1H), 7.79 (dd, 1H), 7.76 (s, 1H), 7.29 (m, 1H), 7.19 (t, 1H), 6.45 (dd, 1H), 3.43-3.49 (m, 3H), 2.94 (s, 3H), 2.36-2.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5](C(O)=O)[NH:6]2.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Clc1cc(Cl)c2cc[nH]c2c1
Yield: 93.9 %

Procedure:
Dissolve 4,6-dichloro-indole-2-carboxylic acid (1.0 g, 4.35 mmol) in quinoline (25 mL). Add copper powder (100 mg) and heat to 220° C. for 3 hours. Pour the resulting black solution into cold concentrated hydrochloric acid (300 mL) and extract into ethyl ether (500 mL). Filter, wash with 1M hydrochloric acid (2×200 mL), water (100 mL) and dry (MgSO4). Evaporate the solvent in vacuo to give a brown oil (0.76 g). Purify by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound as an amber oil (0.66 g, 81%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cc1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-p-tolyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:32]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol was added 0.19 ml (1.6 mM) of benzyl bromide at room temperature, and the mixture was refluxed under nitrogen for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 40%) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O.[H][H]>>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Product: Cc1cc(C(C)(C)C)cc(C)c1N

Procedure:
contacting the 2-nitro-1,3-dimethyl-5-tertiarybutylbenzene with hydrogen in the presence of a hydrogenation catalyst at a temperature of from about 0° C. to about 200° C. and a pressure of from about 0 psig to about 2000 psig to form 2,6-dimethyl-4-tertiary-butylaniline;
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=O)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH:31]([OH:42])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH3:41])[NH:6]2>CC(O)=O.CO.[Zn]>[Cl:1][C:2]1[C:13]2[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH:31]([OH:42])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH3:41])[NH:6]2
Reactant: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4)c(C)c1
Temperature: 90 °C

Procedure:
4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (50.1 mg, 0.083 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc (15 mL). After it was heated at 90° C. for 1 h, the reaction mixture was cooled to 50° C. and diluted with a mixed solvent of MeOH:DCM (45 mL/5 mL) and filtered. The filtrate was evaporated at 95° C. (the bath temperature) under reduced pressure to dryness. The residue was diluted with a mixed solvent of DCM/MeOH (1:5) and basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (16:10:1) followed by HPLC re-purification afforded the title compound in TFA salt form (9.23 mg, 19%). 1H NMR (DMSO-d6) δ 1.95-2.12 (4H), 2.16 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.19 (m, 2H), 3.50-3.75 (4H), 4.07 (m, 2H), 4.12 (m, 1H), 4.30 (s, 1H), 4.49 (s, 2H), 6.22 (m, 1H), 6.80-6.95 (3H), 7.40 (1H), 7.95 (s, 1H), 9.64 (br s, 1H), 11.02 (br s, H, NH), 11.29 (br s, 1H, NH); ESI-MS m/z 591.3 (MH+).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([NH:28][C:18]([CH:16]1[CH2:15][C:14](=[O:13])[CH2:17]1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Yield: 89.9 %

Procedure:
CDI (10.2 g, 0.063 mol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (6 g, 0.052 mol) in THF (60 ml) at 0° C. under stirring, the mixture was stirred at RT for 1 h. Benzylamine (6.9 ml, 0.063 mol) was added to the mixture and the mixture was stirred at RT for 3 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 300 g, CHCl3/MeOH 100:0→95:5) to give the title compound (9.5 g, 89%) as white crystals. LC/MS data: 204.0, 205.1 (M+H) (calculated for C12H13NO2 203.24). 1H NMR data (DMSO-d6): 8.62 (br.s, 1H, NH); 7.21-7.36 (m, 5H, Ph); 4.32 (d, 2H, CH2, J=6.1 Hz); 3.10-3.28 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 72A. mp 168° C.; IR (KBr) cm−1: 3084, 3039, 1744, 1708, 1244, 1226; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.57-7.67 (m, 2H) 7.37 (dd, 1H, J=8.3, 2.0 Hz), 7.01-7.14 (m, 3H), 6.82-6.89 (m, 2H), 6.56 (d, 1H, J=8.4 Hz), 5.04 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 1.88 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53. found: C, 61.13; H, 4.38.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38](Cl)(=[O:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
To a suspension of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (198 mg, 0.4 mmol) in dichloromethane (1 mL) was added acetyl chloride (43 μL, 0.6 mmol) and the mixture was stirred at room temperature for 20 minutes. This reaction mixture was diluted with dichloromethane (3 mL) and, after saturated aqueous NaHCO3 solution (2 mL) was added, the mixture was further stirred. The aqueous layer was then separated and the organic layer was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized from dichloromethane-ethanol and recrystallized from chloroform-ethanol to provide 72 mg (yield 34%) of the title compound. m.p. 303°-306° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].C(O[C:13](=[O:15])[CH3:14])(=O)C>>[CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([O:6][C:13](=[O:15])[CH2:14][CH:2]([CH3:1])[CH2:3][CH3:4])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)CC(=O)O
Product: CCC(C)CC(=O)OC(=O)CC(C)CC
Yield: 97 %

Procedure:
3-Methylpentanoic acid anhydride was prepared from 6 moles of 3-methylpentanoic acid and 4.5 moles of acetic acid anhydride, by distilling acetic acid and the excess acetic acid anhydride from the reaction mixture at atmospheric pressure to a pot temperature of 220° C. Thereafter the desired anhydride was purified by distillation under reduced pressure. Yield: 97% of theory.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10]C.[CH3:14]C(C)/C=C/C(=O)C>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH:9]([CH3:10])[CH3:14]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(=O)/C=C/C(C)C
Product: Cc1cc(C(C)C)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 2, steps 1 and 2) from (3E)-5-methyl-3-hexen-2-one (20 g, 137 mmol). LCMS E-S (M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.86-7.96 (br s, 3H), 6.10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=O)=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:23]3[CH2:26][CH2:25][CH2:24]3)=[O:21])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 2.54 mmol), azetidine (206 μl, 3.05 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.75 ml, 6.36 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.63 mmol) in tetrahydrofuran (20 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was triturated with sat. sodium hydrogencarbonate solution. The solid was filtered off, washed with water and dried in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (910 mg, 88.5%) as a light yellow solid. mp: >250° C., MS: m/z=402.2/404.0 (M−H+)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN(C=O)C>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCN(C(C)=O)CC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
To a suspension of 2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.35 g, 0.81 mmol) in anhydrous DMF (9 mL) was added 1-acetylpyperazine (0.31 g, 2.42 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 32 hours. Solvent was removed under reduced pressure and water (50 mL) was added. The separated solid was filtered, washed with water and ether, and dried under vacuum, to give the title compound as a white solid. Yield: 0.28 g (72%). MP 213-214° C. 1H NMR (400 MHz, CDCl3): δ 9.87 (br s, 1H), 7.74 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.95 (t, J=6.0 Hz, 2H), 3.93 (s, 3H), 3.69 (t, J=5.0 Hz, 2H), 3.53 (t, J=5.0 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.0 Hz, 2H), 2.57 (t, J=5.0 Hz, 2H), 2.39 (s, 6H), 2.11 (s, 3H). MS (ES−) m/z 479.65 (100%, M−1).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Li].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)C>C1COCC1>[CH2:1]([O:7][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: CCCCCC
Reactant: C/C=C/C=C/CO
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C/C=C/COC/C=C/C=C/C

Procedure:
A mixture of 10 g of the polymer from Example 17, 2.2 ml of sorbyl alcohol (2,4-hexadienol) and 0.1 g of lithium metal in 100 ml of THF was refluxed under nitrogen for 18 hours. The mixture was then cooled and a 10-ml portion was poured into 100 ml of hexane containing 2 ml of ethanol to obtain the solid product. To further purify, it was redissolved in 10 ml of THF and suction filtered through a fine frit into 100 ml of water. The precipitated solid was collected and dried.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7]/[C:8](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9]\[CH2:10]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[O:1]=[C:2]([CH3:6])[C:3]([O:5][CH2:10]/[CH:9]=[C:8](\[CH3:7])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[O:4]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-oxopropanoic acid (3.40 g, 38.6 mmol), DMAP (0.48 g, 3.9 mmol) and (E)-3,7-dimethyl-2,6-octadienol (10.00 g, 64.8 mmol) in dichloromethane (90 ml) was cooled on an ice-bath before a solution of DCC (9.18 g, 44.5 mmol) in dichloromethane (45 ml) was added during 30 min. The reaction mixture was stirred for 10 min at 0° C., then at room temperature for ca. 5 h. The precipitate formed in the reaction was filtered off and the filtrate taken up in ether, washed with water (3×), HCl (10%, 3×), a saturated solution of NaHCO3 (3×) and water. The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/ether 4:1) gave 4.68 g (53%) of a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]O)=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][Br:15])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCO)c2n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc2ncn(CCBr)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
17.92 g (0.1 mole) of 2-amino-9-(2-hydroxyethyl)purine was completely dissolved in 200 ml of 1,4-dioxane. The solution was added with 49.75 g (0.15 mole) of carbon tetrabromide and cooled below 5° C. To the cooled material, 39.34 g (0.15 mole) of triphenylphosphine was added, followed by stirring for 5 hours at room temperature. After completion of the reaction, 300 ml of water was added to the reaction product, which was then extracted four times with 500 ml portions of a mixed solution of chloroform and methanol (4:1). The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure, and crystallized from chloroform, 15.74 g (65%) of white 2-amino-9-(2-bromoethyl)purine.