Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N(C)CCO)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 152 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.91 min, m/z=447.0 [M+H]+.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:12][O:13][CH:7]12)(=O)=O.[N:25]([Na])=[N+:26]=[N-:27]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:6]1[CH:7]2[O:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH:8]2[O:9][CH2:10]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=N[Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
To a solution of 6-(1,3-dioxoisoindolin-2-yl)hexahydrofuro[3,2-b]furan-3-yl methanesulfonate (2.80 g, 7.9 mmol) in DMF (60 mL) was added azido sodium (2.16 g, 33.2 mmol). The reaction was allowed to warm to 140° C. for 23 h. The solution was diluted with CH2Cl2 (100 mL), washed with water (100 mL×3) and dried over anhydrous Na2SO4, and then concentrated in vacuo to give the crude product. The product was used for next step without further purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17]>>[OH:4][CH2:3][CH2:2][N:1]([CH2:17][CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: CCOc1ccccc1Cl
Product: OCCN(CCO)CCOc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:46]2[CH2:47][CH2:48][N:43]([C:35]3[N:34]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:44][CH2:45]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc(Cn2c(N3CCNCC3)nc3ccccc32)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4n3Cc3ccccc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-benzyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)(=O)[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4]C=1.I.[OH2:23]>>[C:16]1([C:13]2[O:12][C:11]([C:1]3[CH:2]=[CH:7][C:6]([OH:23])=[CH:5][CH:4]=3)=[N:15][N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)c2nnc(-c3ccccc3)o2)cc1
Reactant: O
Agent: I
Product: Oc1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 130 °C

Procedure:
3.5 g (13.89 mmol) of 2-(p-anisoyl)5-phenyl 1,3,4-oxadiazole and 100 mL of concentrated HI aqueous solution was mixed under nitrogen and refluxed at 130° C. for 12 hours. The mixture was cooled down to room temperature and 100 mL of deionized water was added. The precipitate was collected by filtration and dried under vacuum, p-(5-phenyl-1,3,4-oxadiazole-2-yl) phenol was obtained. 1H-NMR (acetone-d6, ppm) δ9.26 (s, 1H), δ8.15 (m, 2H), δ8.06 (d, 2H), δ7.62 (m, 3H), δ7.07 (d, 2H); mp 256.5° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:25][NH2:26].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[C:6]3[C:3]([C:4]([NH2:5])=[N:25][NH:26]3)=[CH:2][CH:9]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
To a 5-mL microwave vial was added 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (270 mg, 0.824 mmol), hydrazine (0.31 mL, 9.9 mmol), Hunig's base (0.576 mL, 3.30 mmol), and ethanol (3 mL). The reaction mixture was heated at 150° C. for 70 minutes in a microwave reactor. LCMS analysis indicated good conversion, so the reaction mixture was concentrated, dissolved in DMSO and purified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA). The product fractions were pooled, then basified with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (117 mg). LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.23 (m, 3H), 2.84 (d, J=4.0 Hz, 3H), 3.02-3.20 (m, 1H), 3.38-3.51 (m, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.07-4.19 (m, 1H), 4.45-4.57 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.61 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.98 (bs, 1H), 11.51 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=576.1 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and benzyl bromide.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>[Ni].CCO>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCN2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A 50 mL round bottom flask was charged with (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine (0.315 g, 1.26 mmol) and EtOH (5 mL). Hydrazine Hydrate (0.278 mL, 8.82 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Morpholin-4-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.220 g, 0.995 mmol, 79% yield).
Reaction SMILES: CC1C=CC(C(C2C=CC(C)=CC=2)C(=O)C(C)C)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].[CH3:37][O:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:37][O:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH2:33])=[O:32])=[CH:41][CH:40]=1
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(Nc2cccc(C(N)=O)c2)cc1
Temperature: 100 °C

Procedure:
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with Pd2 dba3 (9.2 mg, 0.01 mmol, 2 mol % Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), K2CO3 (304 mg, 2.2 mmol), 3-chloro-benzamide (156 mg, 1.0 mmol), and 4-methoxy-aniline (148 mg, 1.2 mmol). The flask was evacuated and backfilled with argon (3×) and then capped with a rubber septum. To the flask was added t-BuOH (2.5 mL). The septum was replaced with a Teflon screwcap, the flask was sealed, and the mixture was heated to 100° C. with stirring until the starting aryl chloride was consumed by TLC analysis (20 h). The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with EtOAc/hexanes, 8.5:1.5) to give the desired product which was re-crystallized from ethyl acetate/hexanes (14/1) to give white flaky crystals (191 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:16]2)=[C:10]([CH3:11])[N:9]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4sccc4Br)n3n2)cc1
Yield: 22.7 %

Procedure:
Applying the Cyclization Procedure 1, using 3-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 49) (159 mg, 0.37 mmol), 1,2-dichloroethane (7.3 mL) and phosphorus oxychloride (0.273 mL, 2.93 mmol), to afford 7-(3-bromo-2-thienyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 416/418 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].CC(C)=[O:19]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:19][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1CO
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
(E)-Methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (15 g) was dissolved in acetone (200 ml) and the solution was cooled to 2° C. A solution of silver nitrate (22.35 g) in water (200 ml) at 4° C. was added to this. The temperature rose to 12° C. After stirring for 40 minutes the green/grey precipitate which had formed was filtered off and the filtrate partitioned between water and diethyl ether. The diethyl ether layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give an oil which was purified by chromatography on silica gel, eluting with diethyl ether, to give (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate as a viscous oil (6.33 g, 54%). 1H NMR (CDCl3): 2.3(t,1H), 3.7(s,3H) 3.8(s,3H), 4.5(d,2H), 7.1(m,1H), 7.2-7.4(m,2H), 7.5(m,1H), 7.6(s,1H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Preparation of 26—To a solution of 4-tert-butyl-3-methoxy-benzoic acid (3 g, 14.4 mmol, CASRN 79822-46-1) and THF (60 mL) cooled to 0° C. was added a solution of LiAlH4 in THF (29 mL, 28.8 mmol, 1M THF solution). The reaction was stirred overnight at RT then quenched by dropwise addition of aqueous THF (1.1 mL of water in 10 mL of THF) followed by 1.1 mL of 15% NaOH and then 3.3 mL of water. The reaction was stirred for 1 h then solid Na2SO4 was added and the resulting suspension stirred overnight, filtered through a pad of CELITE, and evaporated to afford 2.8 g of 4-tert-butyl-3-methoxy-benzyl alcohol.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.CN(C)CCN>[Cu]I>[N:18]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1)=[N+:19]=[N-:20]
Reactant: COc1ccc(COc2ccc(I)cn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: COc1ccc(COc2ccc(N=[N+]=[N-])cn2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5-Iodo-2-(4′-methoxybenzyloxy)pyridine from step 1 of this example (682 mg, 2.0 mmol), sodium azide (260 mg, 4.00 mmol), copper (1) iodide (38.1 mg, 0.200 mmol) and L-ascorbic acid sodium salt (19.81 mg, 0.100 mmol) were added to a sealable high pressure vessel. The vessel was evacuated and purged with nitrogen, then ethanol (2.75 ml) and water (1.25 ml) were added. N,N-dimethylethylenediamine (31.9 μl, 0.300 mmol) was then added via microliter syringe. The top was sealed and the reaction heated to 100° C. A safety shield was placed in front of the reaction as a precaution. After 90 minutes, the reaction was cooled to room temperature. Reaction was judged to be complete by TLC, so the reaction was partitioned between ethyl acetate and water. The aqueous was extracted again with ethyl acetate, and the combined organics washed again with water. The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The material was purified by column chromatography on a Biotage 40 g SiO2 column, eluting with 5-25% ethyl acetate/heptane to give the title compound as a light tan solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[CH3:27][NH2:28]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:28][CH3:27])[N:11]=1
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CCO
Product: CN=C(NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole (0.25 g.) in ethanol (1 ml.) was added ethanolic methylamine (33% w/v, 30 ml.). The mixture was allowed to stand overnight at room temperature and then evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylguanidino)pentyl]thiazole. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.5 (multiplet, 6H); 2.7 (doublet, 3H); 3.1 (multiplet, 2H); 4.1 (multiplet, 2H); 6.4 (singlet, 1H).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH3:41][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O:31][CH3:41])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (4.23 g, 10 mmol) in a mixture of CH2Cl2 (50 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.00 ml, 10.00 mmol). The solution was stirred at rt for 2 h under nitrogen. LC/MS showed no SM left. The reaction mixture was concentrated to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (4.37 g, 100%). The compound was used in the next step without further purification. LCMS: m/e 559.4 (MH+), 3.29 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.22 (m, J=8.6 Hz, 2H), 5.22-5.39 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.49-4.67 (m, 1H), 3.94 (s, 3H), 3.87 (s, 1H), 3.38 (d, J=10.6 Hz, 1H), 2.37-2.60 (m, 1H), 2.05-2.21 (m, 1H), 1.96 (d, J=11.1 Hz, 2H), 1.90 (d, J=13.1 Hz, 1H), 1.61-1.82 (m, 7H), 1.55 (br. s., 8H), 1.37-1.52 (m, 2H), 1.18-1.37 (m, 4H), 1.08-1.18 (m, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([O:6]C)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]>>[CH3:9][O:8][CH:3]([O:2][CH3:1])[C:4]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([O:11][CH3:10])[CH:13]=1)=[O:6]
Reactant: COC(=O)C(OC)OC
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)C(OC)OC)c1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
Into a vial was added methyl dimethoxyacetate (2.0 g, 14 mmol) and 3-methoxybenzylamine (2.0 g, 14 mmol), this mixture was stirred at room temperature for 8 d. The product was triturated with heptane (3×) and then dried in vacuo, yielding the desired product as an off-white solid. MS (ES+): m/z=240.84 [MH+]. HPLC: tR=2.55 min (ZQ2, polar—5 min).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@@H:2]([C:13]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Z-DTrp-OH (3.21 g) and βAla-OEt.HCl (1.49 g) were suspended in dichloromethane (30 ml), and N-methylmorpholine (1.05 g) and HOBT.H2O (1.59 g) were added at room temperature, and then EDCI.HCl (11.99 g) was added at 0°~5° C. The reaction mixture was stirred at room temperature overnight, diluted with dichloro-methane, washed successively with sat. NaHCO3, 1N HCl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with dichloromethane/methanol=30/1 for elution to give the product (3.02 g).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1([C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:10][O:9][CH2:8][O:7][CH2:6]1.Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[CH:21]1([CH2:20][CH:12]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:11]([C:5]2([CH3:4])[CH2:10][O:9][CH2:8][O:7][CH2:6]2)=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Reactant: BrCC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C(=O)C(CC2CCCCC2)n2cncn2)COCOC1
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
2.96 g (0.05 mol) of powdered potassium hydroxide and 3 ml of water are added to a solution of 11.0 g (0.05 mol) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 40 ml of dimethylsulphoxide, with stirring. After 10 minutes, 9.6 g (0.05 mol) of bromomethylcyclohexane (90% pure) are added and the mixture is stirred at 50° C. for 6 hours. For working up, the cooled reaction mixture is poured onto 500 ml of water and extracted twice with 200 ml of diethyl ether each time, the combined ether extracts are washed twice with 100 ml of water each time and dried over sodium sulphate and the solvent is removed in vacuo. The oily residue crystallizes from methylene chloride/diethyl ether. 8.0 g (52.1 g of theory) of 3-cyclohexyl-1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-propan-1-one of melting point 68°-71 ° C. are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[CH:12]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1>C(Cl)Cl>[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17](=[O:19])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=3)[CH:14]=[C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1cc2c(OCC(C)C)cc(C(=O)O)cc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
Oxalyl chloride (410 mg, 282 μl, 3.225 mmol, 5 eq) was added to a solution of 2-methyl-4-isobutoxy-6-carboxybenzofuran (Method 2; 0.160 mg, 0.645 mmol) in DCM (5 ml) and the reaction mixture stirred for 4 hrs at ambient temperature. Further reagent was added, the reaction mixture stirred for 16 hrs, and then warmed to 40° C. As starting acid still remained, the solvent was removed in vacuo and the residue treated with neat oxalyl chloride. The reaction mixture was then concentrated in vacuo and dissolved in pyridine (5 ml); to the resulting solution was added methyl 2-aminopyridine-5-carboxylate (98 mg, 0.645 mmol). After stirring for 16 hrs the reddish solution was concentrated in vacuo and the resulting gum dissolved in DCM and chromatographed (20 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound (122 mg, 49.5% yield) as a colourless gum which slowly set solid; LC-MS 383 (M+H)+, 94.4% strength.