Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][C@H:24]([C:44]([OH:46])=[O:45])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:38][C:39]3[S:40][CH:41]=[CH:42][N:43]=3)[CH2:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccs1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](N)C(=O)O)Cc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Piperidine (0.20 mL) was added to a solution of (S)-1-(9H-fluoren-9-yl)-14,14-dimethyl-3,12-dioxo-10-(thiazol-2-ylmethyl)-2,13-dioxa-4,10-diazapentadecane-5-carboxylic acid (72.5 mg, 0.125 mmol) in DMF (1.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by flash chromatography over silica gel to afford (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)(thiazol-2-ylmethyl)amino)hexanoic acid (25 mg, 35%). 1H NMR (400 MHz, CD3OD) 7.70 (d, J=3.6 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 4.15 (s, 2H), 3.52 (dd, J=7.2, 5.2 Hz, 1H), 3.38 (s, 2H), 2.73 (t, J=7.2 Hz, 2H), 1.91-1.76 (m, 2H), 1.60-1.44 (m, 13H); MS (ESI), 358 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24]O)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:61].N1C=CC=CC=1.O>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][Cl:61])[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Temperature: -20 °C
Yield: 112.4 %

Procedure:
To a solution of benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate (100 g) in methylene chloride (600 ml) was added at a time phosphorus pentachloride (25.6 g) at -30° C., followed by adding dropwise pyridine (9.8 g) at the same temperature. After the reaction mixture was stirred at -20° C. for an hour, it was poured into a mixture of methylene chloride (500 ml) and water (300 ml). The separated organic layer was washed with an aqueous sodium chloride, dried over magnesium sulfate and then evaporated to dryness to obtain benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate (114.5 g), mp 90°-110° C. (dec.).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:13]=[C:12]([CH3:25])[CH:11]=1)(=O)C.[ClH:26]>CO>[ClH:26].[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:25])=[N:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2cccc(C(F)(F)F)c2)n1

Procedure:
1-Acetyl-2[1-(3-Trifluoromethylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (13.0 g.) was treated with HCl in methanol as described in Example II to give 10.12 g. of product as the HCl salt, mp 205°-206°.
Reaction SMILES: [CH2:1]([O:8][P:9]([CH2:18][C@H:19]([OH:43])[CH2:20][NH:21][C:22](=[O:42])[C@@H:23]([NH:27][C:28](=[O:41])[C@@H:29]([NH:33]C(OC(C)(C)C)=O)[CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:26])[CH3:25])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]([NH:54][C@H:55]([C:59]([OH:61])=O)[CH:56]([CH3:58])[CH3:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[CH2:1]([O:8][P:9]([CH2:18][C@H:19]([OH:43])[CH2:20][NH:21][C:22](=[O:42])[C@@H:23]([NH:27][C:28](=[O:41])[C@@H:29]([NH:33][C:59](=[O:61])[C@@H:55]([NH:54][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[CH:56]([CH3:57])[CH3:58])[CH:30]([CH3:31])[CH3:32])[CH:24]([CH3:25])[CH3:26])([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C)C(C)C

Procedure:
The resulting product from Step 1 was deprotected in a similar manner as Example 1, step 3, and the compound was used immediately and coupled to N-Cbz-L-valine in accordance with the procedures set forth in Example 12, Method B. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a RediSep disposable column. 1H NMR (CD3Cl, 300 MHz): δ 7.45-7.25 (m, 10H), 6.0-5.85 (m, 1H), 5.18-4.92 (m, 4H), 4.50-4.33 (m, 2H), 4.31-4.04 (m, 2H), 3.43-3.26 (m, 2H), 2.25-2.03 (m, 3H), 2.02-1.70 (m, 8H), 1.37-1.10 (m, 4H), 1.04-0.82 (m, 20H). LCMS m/z: [M+H]+=757.9.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])\[CH3:8])(=[O:3])[CH3:2].C([O:19]O)(C)(C)C.C(O)(=O)C1C(=CC=CC=1)O>[Al].C1(C)C=CC=CC=1.C(Cl)Cl.O=[Mn]=O>[CH3:8]/[C:7](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:14])/[CH:13]=[O:19])=[CH:6]\[CH2:5][O:4][C:1]([CH3:2])=[O:3]
Reactant: CC(=O)OC/C=C(\C)CCC=C(C)C
Reactant: CC(C)(C)OO
Agent: O=[Mn]=O
Agent: O=C(O)c1ccccc1O
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC/C=C(\C)CC/C=C(\C)C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
Geranyl acetate was oxidized as described previously with some modification (21). Forty milliliters (0.36 mol) of 90% tert-butyl hydroperoxide was added to a stirred suspension of 1.11 g (0.01 mol) of SeO2, 1.4 g (0.01 mol) of salicylic acid, and 75 ml of CH2Cl2 in a 250 ml round bottom flask covered in aluminum foil. The resulting solution was allowed to stir to homogeneity at room temperature before being placed at 0° C. After ten minutes, 21.5 ml (0.10 mol) of geranyl acetate (4) was introduced dropwise. The mixture was stirred for 5 h at 0° C., and then for 20 h at rt. TLC analysis indicated the presence of starting material and two oxidized products (Rf 0.38 aldehyde, Rf 0.19 alcohol). The solution was diluted with 100 ml toluene, and solvents were removed under reduced pressure. The residue was then dissolved in toluene, washed with 5% NaHCO3 to remove H2SeO3, saturated CuSO4, saturated aqueous Na2S2O3 (2×), water, brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure affording a crude oil, which was dissolved in 100 ml dry CH2Cl2 and cooled to 0° C. 40.95 g (0.47 mol) of activated MnO2 was added, and the suspension was stirred for 5 h at 0° C., then overnight at rt. The mixture was filtered over a short bed of Celite, and washed thoroughly with dry CH2Cl2. Solvent was evaporated under reduced pressure to yield a crude, pale yellow oil which was purified by flash chromatography on silica gel (5% EtOAc in hexane) affording 10.68 g (51 %) of 5 as a colorless oil; 1H NMR (C6H6, 200 MHz) δ9.47 (s, 1H), 5.98 (t, 1H, J=6.9 Hz), 5.48 (t, 1H, J=6.9 Hz), 4.75 (d, 2H, J=6.8 Hz), 2.11 (q, 2H, J=7.3 Hz), 1.92 (t, 2H, J=7.3 Hz), 1.91 (s, 3H), 1.79 (s, 6H), 1.59 (s, 3H); 13C NMR (50.3 MHz) δ195.47, 171.39, 153.70, 140.73, 140.08, 120.01, 61.48, 38.13, 27.33, 21.37, 16.77, 9.62.
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.[Cl:16][C:17]1[CH:24]=[C:21]([CH:22]=[O:23])[C:20]([OH:25])=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-chloro-salicylaldehyde (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. for 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 5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4]C=1.[CH3:9][N:10]([CH3:16])[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C([N:19](C(C)C)C(C)C)C.Cl>C(O)CCC.CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][CH:11]([N:10]([CH3:16])[CH3:9])[CH2:12]2)=[N:19][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C1CCNC1
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C1CCN(c2ccc(Br)cn2)C1

Procedure:
A solution of 215 mg (0.88 mmol) 2,5-dibromobenzene, 100 mg (0.88 mmol) 3-(dimethylamino)-pyrrolidine and 0.60 mL (3.51 mmol) ethyldiisopropylamine in 0.5 mL n-butanol is stirred for 30 min in the microwave at 150° C. The solvent is eliminated i.vac. and the residue is taken up in 20 mL EtOAc and 10 mL water. The aqueous phase is acidified with 1 M HCl. The phases are separated and then the aqueous phase is made alkaline with 2 M Na2CO3 solution and extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:58][C:59]1[S:60][CH:61]=[CH:62][N:63]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:58][C:59]2[S:60][CH:61]=[CH:62][N:63]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 57 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid (157 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (113 mg, 57.1%) as a white solid: mp 172-174° C.; EI-HRMS m/e calcd for C23H28N2O2S (M+) 396.1871, found 396.1866.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C(OC(=O)[N:27]([C:37]1[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[C:39]([CH3:45])[N:38]=1)[CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(C)(C)C>>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([CH2:28][NH:27][C:37]2[N:38]=[C:39]([CH3:45])[C:40]([C:43]([C:2]3[C:10]4[CH:9]=[N:8][CH:7]=[N:6][C:5]=4[NH:4][CH:3]=3)=[O:44])=[CH:41][CH:42]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(C)n2)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)c(C)n2)cn1

Procedure:
{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2-methyl-pyridin-3-yl}-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-0019 was prepared in two steps from 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 38 and (5-formyl-6-methyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 74 as shown in Scheme 14.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:32][CH3:33])[CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([OH:24])=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:32][CH3:33])[CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)O

Procedure:
A solution of 6.7 g. of benzyl 9-benzoyl-6-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 250 ml. of ethyl acetate was hydrogenated over 1 g. of palladium-on-charcoal until the required amount of hydrogen had reacted. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was slurried in ether and the resulting solid was collected by filtration to give 1.8 g. of the title compound; m.p. 157-159°C.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[NH:21][CH2:22][CH2:23][CH2:24][N:25]=1.[O:26]1C2C3OC(CNCCCNC4NCCCN=4)CCC=3C=CC=2OCC1>>[O:1]1[CH:2]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[NH:21][CH2:22][CH2:23][CH2:24][N:25]=2)[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH2:13][O:26][C:7]=3[C:6]1=2
Reactant: c1cc2c(c3c1CCC(CNCCCNC1=NCCCN1)O3)OCCO2
Reactant: c1cc2c(c3c1CCC3)OC(CNCCCNC1=NCCCN1)CC2
Product: c1cc2c(c3c1CCCO3)OC(CNCCCNC1=NCCCN1)CC2

Procedure:
N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;
Reaction SMILES: C([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.OS(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[C:17](=[O:26])[NH:16][C:15](=[O:27])[NH:14][CH:19]=2)[CH:21]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1cccnc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1[nH]cc(-c2cccnc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 3), starting from 1-benzhydryl-5-(3-pyridyl)pyrimidine-2,4-dione (0.085 g, 0.239 mmol). Herein, anisole (0.163 g, 1.5 mmol) was added together with the triflic acid/TFA mixture, and the orange reaction mixture was here stirred for 1 hr at 0° C. TFA was removed by a stream of nitrogen and remaining TFA removed by co-evaporating with diethyl ether (40 mL). Water (15 mL) and acetonitrile (15 mL) was added, solidified in a dry ice-acetone bath, and the crude title compound was obtained by lyophilization. The crude was purified by column chromatography using a Teledyne ISCO apparatus (Dichloromethane:20% methanol in dichloromethane 30:70) to afford the title compound as, a triflic salt (0.067 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.91 (dd, J=6.2, 5.8 Hz, 1H), 8.07 (d, J=6.1 Hz, 1H), 8.60 (dt, J=8.2, 1.6 Hz, 1H), 8.72 (dd, J=5.4, 1.4 Hz, 1H), 9.06 (d, J=2.1 Hz, 1H), 11.55 (s, 1H), 11.58 (d, =5.5 Hz, 1H). MS (ESI) m/z: 190 [M-H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(Nc2cc(-c3cc(Cl)ccc3C)nc(N)n2)cc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a stirred suspension of the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine (0.01 g, 0.0344 mmol) in ethanol (5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.01 ml) followed by p-tolylamine (0.074 g, 0.068 mmol). The mixture was heated under reflux for 75 minutes. After evaporation of volatiles under reduced pressure, the residue was treated 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. After filtration the solid was dissolved in methanol (5 ml) and treated with a solution of sodium carbonate in water (1.0 M, 1.0 ml). After stirring for 30 minutes volatiles were evaporated under reduced pressure. The residue was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.011 g, 98% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 6.07 (s, 1H, Ar), 6.33 (s, 2H, NH2), 7.10 (d, 2H, J=8.3 Hz, Ar), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.35-7.40 (m, 2H, Ar), 7.61 (d, 1H, J=8.4 Hz, Ar), 9.09 (s, 1H, NH).
Reaction SMILES: CC(C)([O-])C.[K+].C([Si](C)(C)[C:12]#[C:13][CH2:14][N:15]1[C:20]2[N:21]=[C:22](S(C)(=O)=O)[N:23]=[CH:24][C:19]=2[CH:18]=[C:17]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[C:16]1=[O:37])(C)(C)C.[N:40]1[S:41][N:42]=[C:43]2[CH:48]=[C:47]([NH2:49])[CH:46]=[CH:45][C:44]=12>CS(C)=O.O.C(OCC)(=O)C>[N:40]1[S:41][N:42]=[C:43]2[CH:48]=[C:47]([NH:49][C:22]3[N:23]=[CH:24][C:19]4[CH:18]=[C:17]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:36])[C:16](=[O:37])[N:15]([CH2:14][C:13]#[CH:12])[C:20]=4[N:21]=3)[CH:46]=[CH:45][C:44]=12
Reactant: Nc1ccc2nsnc2c1
Reactant: CC(C)(C)[Si](C)(C)C#CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc21

Procedure:
62 mg of potassium tert-butoxide are added in 3 installments, at ambient temperature under argon, to 180 mg of compound of formula (II), described below, 8-[3-((tert-butyl)dimethylsilanyl)prop-2-ynyl]-6-(2,6-dichlorophenyl)-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 81 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in solution in 5 ml of DMSO. After a contact time of 75 min, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is brought back to neutral pH and extracted with dichloromethane. After drying the organic phase over sodium sulfate and filtering, the residue is chromatographed on silica (gradient: CH2Cl2 100 to CH2Cl2/MeOH 98:2) to give 52 mg of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>ClCCl>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([C:8]#[N:9])=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Br
Temperature: 25 °C

Procedure:
tert-Butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (100 mg, 0.253 mmol) was suspended in dichloromethane (1 mL). TFA (0.390 mL, 5.06 mmol) was added, and the reaction mixture was maintained at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-bromopyridine-2-carbonitrile TFA salt. The material was used without further purification in the subsequent transformation. MS ESI calc'd. for C12H16BrN4 [M+H]+ 295 and 297. found 295 and 297.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[O:8][C:7]=12.C([Li])CCC.[C:17](=[O:19])=[O:18]>C(OCC)C>[CH3:11][C:9]1[O:8][C:7]2=[C:2]([C:17]([OH:19])=[O:18])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1
Reactant: O=C=O
Reactant: Cc1cc2ccnc(Br)c2o1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc2ccnc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-2-methylfurano[2,3-c]pyridine (1.76 g) in dry diethyl ether (45 ml) under an atmosphere of nitrogen, was cooled to -78° C. and treated with n-butyllithium (1.6M in hexane) (5.8 ml). After stirring for 2 hours, the reaction mixture was poured onto a mixture of solid carbon dioxide pellets and diethyl ether (5 ml). After warming to room temperature, the solvent was removed under reduced pressure. The residue was triturated with diethyl ether and filtered to give the title compound as a pale pink powder 1.45 g.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.O>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCCBr)no1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.5 g, 24 mmol) in N,N-dimethylformamide (20 mL) was treated with potassium carbonate (6.8 g, 49 mmol) and 1,3-dibromopropane (2.5 mL, 24 mmol) was added and the mixture was stirred at 40° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% ethyl acetate/hexanes) to give the desired product (1.6 g, 25%). MF=C8H11BrNO4; LCMS calculated for C8H11BrNO4 (M+H)+: m/z=264.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C(O)C>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:12]
Reactant: CCSC(=S)Nc1ccccn1
Reactant: CN(C)CCCN
Solvent: CCO
Product: CN(C)CCCNC(=S)Nc1ccccn1

Procedure:
A mixture of ethyl 2-pyridyldithiocarbamate (600 mg), 3-(dimethylamino)propylamine (0.38 ml) and ethanol (6 ml) was heated with reflux under nitrogen atmosphere. One and half hour thereafter, the reaction mixture was concentrated under reduced pressure to give the title compound (786 mg) as crude oil.