Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:33][NH2:34])(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:34]/[NH:33][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: NNC(=O)c1ccncc1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: C/C(=N\NC(=O)c1ccncc1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 70.2 %

Procedure:
The title compound (27.9 mg, 64%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) and isonicotinic acid hydrazide (38.3 mg, 0.28 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.75, 11.39 (bs, 1H), 9.51 (s, 1H), 8.93 (dd, 1H), 8.79 (m, 2H), 8.42 (d, 1H), 8.20 (d, 1H), 7.836 (m, 3H), 7.54 (dd, 1H), 6.25 (s, 2H), 2.49 (s, 3H). LCMS (method E): [MH]+=442, tR=4.59 min.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH2:17][N:33]1[CH2:34][CH2:35][CH:30]([C:26]2[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Product: CC(C)CCOc1ccc2ccccc2c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 2-(isopentyloxy)-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 110 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
In DMF (50 ml) was dissolved methyl 5-nitrosalicylate (1.97 g, 10.0 mmol), and to the mixture were added ethyl 4-bromobutyrate (1.57 ml, 11.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol). The mixture was stirred at 110° C. for 5 hours, and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and 10% potassium carbonate solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate/hexane=1/5→1/3), and the desired fraction was concentrated under reduced pressure to give ethyl 4-(2-methoxycarbonyl-4-nitrophenoxy)butyrate (2.51 g, 8.06 mmol, 81%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCCOc1ccccc1)c1cc(O)ccc1O
Reaction time: 12 h

Procedure:
A solution of 4-(2,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields the desired product.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]2=[CH:5][CH:4]=1)[NH2:2].[C:15](/[N:17]=[C:18](\OC1C=CC=CC=1)/[NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)#[N:16]>C(O)(C)C>[N:8]1[C:3]([N:1]2[C:15]([NH2:16])=[N:17][C:18]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)=[N:2]2)=[CH:4][CH:5]=[C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=12
Reactant: CN1CCN(c2ccc(N/C(=N/C#N)Oc3ccccc3)cc2)CC1
Reactant: NNc1ccc2c(n1)CCCCCC2
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(N)n(-c4ccc5c(n4)CCCCCC5)n3)cc2)CC1

Procedure:
2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (81 mg, 0.42 mmol) and (Z)-phenyl N′-cyano-N-(4-(4-methylpiperazin-1-yl)phenyl)carbamimidate (142 mg, 0.42 mmol) were suspended in isopropanol and subjected to microwave irradiation (150° C., 20 min). The crude product was purified by C-18 reversed phase HPLC to give 1-(5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-yl)-N3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #23, as a white solid, 92 mg; 1H NMR (DMSO-d6, 300 MHz) 8.69 (s, 1H), 8.13 (s, 1H), 7.65 (d, 1H), 7.55 (s, 1H), 7.44 (d, 2H), 7.41 (d, 1H), 6.84 (d, 2H), 3.01 (m, 4H), 2.90 (m, 2H), 2.75 (m, 2H), 2.50 (m, 4H), 2.25 (s, 3H), 1.71 (m, 2H), 1.63 (m, 2H), 1.33 (m, 4H) ppm; MS (ES) 433.17 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19N5O3S, 385.12; m/z found, 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.92 (s, 2H), 8.60 (dd, J=2.3, 0.8, 1H), 8.09 (dd, J=8.0, 1.3, 1H), 7.91 (dd, J=8.2, 2.3, 1H), 7.82 (dd, J=8.2, 0.9, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.41 (dd, J=7.6, 1.4, 1H), 3.70-3.59 (m, 1H), 2.79-2.67 (m, 2H), 1.04 (d, J=6.3, 3H).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:24].P(Cl)(Cl)(Cl)=O>>[Cl:24][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 6.34 gm. (20 mmole) of finely powdered methyl 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylate 5,5-dioxide to a mixture of 6.25 gm. (30 mmole) phosphorous pentachloride in 17.3 ml. of phosphoryl chloride. Stir for 18 hours at room temperature. Separate the solids by filtration, wash with ether and dry in vacuo over potassium hydroxide. Dissolve the crude product in boiling tetrahydrofuran, filter and evaporate to a small volume in a stream of nitrogen. Dilute with acetonitrile and separate the precipitate by filtration in order to obtain the title product. (m.p. 254°-256° C.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[C:7](#[N:10])[CH:8]=[CH2:9].Cl>CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:9][CH2:8][C:7]#[N:10])[CH3:2]
Reactant: CCOCCO
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Product: CCOCCOCCC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
To an ice-water cooled mixture of 2-ethoxyethanol (1 g, 11.1 mmol) and Triton B (40% in MeOH, 0.138 g, 0.33 mmol) was added acrylonitrile (0.618 g, 11.6 mmol) and the mixture was stirred at room temperature for 24 hours. It was then neutralized with 0.1 M HCl (3.3 cm3) and extracted with CH2Cl2 (2×10 cm3) The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give the product 3-(2-ethoxyethoxy)propanenitrile (1.20 g, 75.5%) as a colorless oil, bp 100-130° C./20 Torr.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:28])[C:4]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:32]>C(Cl)(Cl)Cl>[ClH:32].[CH3:28][N:3]([CH3:2])[C:4]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][CH3:14])[CH2:6][CH2:5]1
Reactant: ClC(Cl)Cl
Reactant: CN(CCCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCCN1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
HCl gas was passed through a solution of 9 g (1 eq.) tert-butyl 3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl(methyl)carbamate in 100 ml chloroform at 0° C. for 1 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and after trituration with diethyl ether 10 g (100%) of product were obtained in the form of a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:32]([C:27]2[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 33; 327 mg, 1.03 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 250 mg, 1.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (211 mg, 1.55 mmol), EDC (297 mg, 1.55 mmol) and triethylamine (0.432 ml, 3.10 mmol) in DCM (4 ml) was stirred at room temperature for 18 hours. The reaction was partitioned between DCM (10 ml) and water (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (0-100% ethyl acetate/petrol) and was then by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10]>CN(C)C=O.O>[N:1]([CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
6 mg of sodium azide was added to 18 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-iodoethyl)ester dissolved in a mixture of 0.2 mL of N,N-dimethylformamide and 0.02 mL of water at room temperature, and the mixture was stirred for 12 hours at 60° C. After standing to cool, the solvent was distilled under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18, eluent:water to a 70% aqueous solution of acetonitrile), thereby yielding 7 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl)ester
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([NH2:13])[CH3:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[N:29]=[C:30](S(C)=O)[O:31][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]>C1COCC1>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[N:29]=[C:30]([NH:13][CH:11]([C:10]4[C:5]5[O:4][CH2:3][CH2:2][O:1][C:6]=5[CH:7]=[CH:8][CH:9]=4)[CH3:12])[O:31][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: CC(N)c1cccc2c1OCCO2
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(C)c4cccc5c4OCCO5)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine (3 eq) in THF was added 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq). This was stirred at room temperature for 8 hours, concentrated and the residue was purified by preparatory reverse phase HPLC. MH+=447.1.
Reaction SMILES: C(OC1C=C(C=CC=1OC)C[N:13]1[C:21]2[N:20]=[C:19](C(OCC3C=CC=CC=3)(C)C)[NH:18][C:17]=2[C:16](=[O:33])[NH:15][C:14]1=S)C1C=CC=CC=1.C(OC1C=C(C=CC=1OC)CN1C2N=C(C(OCC3C=CC=CC=3)(C)C)NC=2C(=O)N=C1)C1C=CC=CC=1.CO>C(O)CC.[Ni]>[NH:15]1[C:16](=[O:33])[C:17]2[NH:18][CH:19]=[N:20][C:21]=2[N:13]=[CH:14]1
Reactant: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Agent: [Ni]
Agent: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Solvent: CCCO
Solvent: CO
Product: O=c1[nH]cnc2nc[nH]c12
Yield: 35.1 %

Procedure:
3-(3-Benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-2-thioxanthine (26.05 g, 48 mmole) was heated under reflux in 1-propanol (700 ml) with Raney-nickel (29 g) (treated with 0.1% aqueous acetic acid) for 1.5 hours. The nickel was filtered off and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (300 ml), extracted with sodium carbonate solution and evaporated again to dryness. The residue was dissolved in methanol (150 ml), treated with charcoal, filtered, concentrated and crystallized to give 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-hypoxanthine (15.81 g, 64.5%), mp 78-86° C. (containing methanol). A second crop gave 2.29 g (9.3%) of hypoxanthine.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[N:11]3[C:12](I)=[CH:13][N:14]=[C:10]3[N:9]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[C:33](=[O:35])=[O:34]>C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[N:11]3[C:12]([C:33]([OH:35])=[O:34])=[CH:13][N:14]=[C:10]3[N:9]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(I)n21
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-(4-bromo-benzyl)-1-(3,5-dichloro-phenyl)-5-iodo-3-methyl-1H-imidazo[1,2-a]imidazol-2-one (4.5 g, 7.8 mmol) in THF (50 mL) was cooled to −40° C. To this was slowly added isopropyl magnesium bromide (1M in THF, 15.6 mL, 15.6 mmol) over 30 min. The reaction mixture was stirred at −40° C. for 1 h and then CO2 gas passed through the solution for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with water. The mixture was acidified with 1N HCl and extracted with CH2Cl2 (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated in vacuo. The residue was dissolved in toluene (40 mL) and hexane was added (100 mL). The resulting precipitate was filtered and washed with hexane to afford 2.6 g of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid as a purple solid, m/z 495.5 [M+]+.
Reaction SMILES: C(O)C.C([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(=O)C)[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)(=O)C>O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1cccc(C#CC=Cc2cccc(NC(C)=O)c2)c1
Solvent: O
Solvent: CCO
Product: Nc1cccc(C#CC=Cc2cccc(N)c2)c1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To 50 ml of a 28% aqueous ethanol solution was added 2.6 g (0.0084 mole) of 1,4-bis-(3-acetamidophenyl)-buta-1-ene-3-yne and the mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into 300 ml of distilled water and extracted with three 100 ml portions of methylene chloride. Removal of the methylene chloride under reduced pressure provided a light yellow material. Recrystallization of the material from a one-to-one mixture of benzene/hexane gave 1 g (50% yield) of product (m.p. 105°-106° C.).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1ccc2c(c1C)OCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OCCS2
Reaction time: 2 h

Procedure:
4.0 g (0.0168 mol) of ethyl 8-methyl-2,3-dihydrobenz-1,4-oxathiine-7-carboxylate together with 1.0 g (0.0252 mol) of sodium hydroxide are refluxed in 40 ml of methanol/water. The mixture is stirred for 2 hours at this temperature, and the solvent is subsequently distilled off. The residue is taken up in water. The mixture is extracted using ether, and the aqueous phase is then acidified using 2 N hydrochloric acid. The product of value precipitates and is filtered off with suction and washed with a small amount of water. The product is dried in a vacuum drying oven at 40° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7](=O)[CH2:8][CH2:9][CH3:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[CH:8][CH2:9][CH3:10]
Reactant: O=C1CCCN1
Reactant: CCCC=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CCC=CN1CCCC1=O

Procedure:
A solution of 2-pyrrolidone (50 g, 0.588 mol), butanal (42.4 g, 0.588 mol) and P2O5 (2 g, 0.014 mol) in 300 ml toluene, were refluxed together for 10 hours using Dean-Stark apparatus to collect liberated water. The resulting solution was cooled and washed with 5% solution of sodium bicarbonate and dried over anhydrous sodium sulphate. After removing the solvent under reduced pressure, 1-(but-1-enyl) pyrrolidin-2-one (I) was obtained by distillation as a liquid. (68.2 g, 83.2%). 1H NMR (CDCl3): δ 1.02 (3H,t), 2.03-2.15 (4H, m), 2.45 (2H, t), 3.5 (2H, t), 5.01 (1H, m), and 6.85 (1H, d). 13C-NMR (CDCl3): δ 172.52, 122.91, 113.8, 45.09, 31.07, 23.03, 17.27, and 14.27. IR: 2962, 2930, 1698, 1663, 1253 Cm−1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:15]=[N:16][C:17]([C:20]4[C:21]([O:26]C)=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CO>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:15]=[N:16][C:17]([C:20]4[C:21]([OH:26])=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1-c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Agent: Cl
Solvent: CO
Product: Oc1ncccc1-c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a 50 mL round bottom flask was added N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine (1.7 g, 4.7 mmol), concentrated hydrochloric acid (15 mL), and methanol (15 mL). The reaction was heated to 90° C. and stirred for 12 h. The reaction was concentrated, brought to pH of 11 through the addition of saturated potassium carbonate (20 mL), and then diluted with ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and washed with lithium chloride (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 3-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)pyridin-2-ol (1.6 g, 95%) as a tan powder. The isolated product (1.3 g, 3.7 mmol, 1.0 equiv) was transferred to a 100 mL round bottom flask, followed by the addition of a mixture of phosphorous oxytrichloride (24 mL) and DMF (8 mL). The reaction was heated to 90° C. and stirred for 6 h. The reaction was concentrated and carefully quenched with a 50% mixture of saturated sodium bicarbonate and lithium chloride until gas evolution ceased. The mixture was extracted with ethyl acetate (100 mL). The combined organic layers were then dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give 1.2 g (88%) of 6-(2-chloropyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:49][C@@H:50]1[CH2:55][NH:54][CH2:53][C@H:52]([CH3:56])[NH:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:53][C@H:52]([CH3:56])[NH:51][C@H:50]([CH3:49])[CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (40 mg, 0.062 mmol), (2R,6S)-2,6-dimethylpiperazine (70.73 mg, 0.619 mmol, 10 eq) and acetic acid (3.55 μL, 0.062 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in a VX-2500 Multi-Tube Vortexer overnight at room temperature. MP-triacetoxyborohydride (195 mg, 0.482 mmol, 7.78 eq) was then added and the mixture was stirred again in the VX-2500 Multi-Tube Vortexer overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on a Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 11.3 mg (27.2%) of the title compound. LC-MS m/z 744 (M+H)+, 1.41 min (ret time).