Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NCC(O)=O)(OC(C)(C)C)=O.C(O)C1C=CC=CC=1>>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: OCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldrich) using General Procedure X, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=167.5° C.). The reaction was monitored by tlc (Rf=0.35 in 2% MeOH/CH2Cl) and the product was purified by flash chromatography using 2% MeOH/CH2Cl2 as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C([O-])(O)=O.[Na+].CN(C=O)C>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and NaHCO3 (8.25 g, 98 mmol) was taken into 130 ml of DMF and heated at 80° C. for 18 h. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of H2O and extracted with Et2O (3×150 ml). The aq. solution was acidified to pH 5 with 10% NaHSO4 and extracted with EtOAc (3×250 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid: 1H NMR (CD3OD) δ8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>C1COCC1.O.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:34])[N:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(S(=O)(=O)c2ccccc2)c2cc(N3CCN(Cc4ccccc4)CC3)ccc21
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A solution of 5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole (433 mg, 1.00 mmol) in THF at room temperature is treated with NaH (80 mg, 60% in mineral oil, 2.00 mmol), stirred for 0.5 h, treated with methyl iodide (142 mg, 1.00 mmol), stirred for 16 h, and diluted with water and EtOAc. The organic phase is separated, dried over MgSO4, and concentrated in vacuo. The resultant residue is chromatographed (SiO2, 90:10 EtOAc:hexanes as eluent) to afford the title compound as a white solid, 190 mg (43% yield), mp 195-197° C., identified by mass spectral and NMR analyses.
Reaction SMILES: S1C=CC=C1C1(N2CCCCC2)CCCCC1.CCC(C[O:24][C:25]([C:38]([N:40]([CH2:42]C[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].[CH3:48][C:49]([OH:51])=[O:50].C(O)C(N)(CO)C[OH:55]>>[CH3:42][NH:40][C@@H:38]([C:25]([OH:24])=[O:55])[CH2:48][C:49]([OH:51])=[O:50]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)O
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: c1csc(C2(N3CCCCC3)CCCCC2)c1
Product: CN[C@H](CC(=O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
The effect on the TCP (1-[1-(2-thienyl)-cyclohexyl]piperidine) binding was measured in rat brain synaptic membranes (SPM) prepared as previously described [J. B. Monahan & J. Michel; J. Neurochem. 48:1699-1708 (1987)]. Prior to their use in the binding assay, frozen SPM were thawed, diluted twenty fold with 50 mM Tris/acetate (pH 7.4 containing 0.04% (v/v) TritOn X-100), incubated for 30 min. at 37° C. and centrifuged at 95,000×g for 15 min. The Triton X-100 treated SPM were washed with 5 mM Tris/HCl, pH 7.4 and centrifuged a total of six times. The compound of Example #7 was incubated at different concentrations with SPM (0.2-0.4 mg protein) and 2 nM tritiated TCP, in a total volume of 0.5 ml of 5 mM Tris/HCl buffer pH 7.4 at 25° C. for 60 min. The samples were filtered through glass fiber filters (Schleicher & Schuell π32) which have been pretreated with 0.05% (v/v) polyethylenimine, washed 4 times with 2 ml of ice-cold 5 mM Tris/HCl buffer, and then counted on a Beckman LS 5800 liquid scintillation counter with automatic corrections for quenching and counting efficiency. Inhibition of TCP binding was measured as a decrease in the binding in the presence of 0.05 mM L-glutamate. Non-specific binding was defined as the residual binding in the presence of 60 mM phencyclidine. Results are shown in Table II.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[CH:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.ClCCl.CO.N>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[C:27][C:2]3[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: C#CC(=O)NCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: OCc1ccc(I)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(CO)cc1)NCc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.a. from 4-iodobenzyl alcohol and propynoic acid-(4′-chlorobiphenyl-4-yl)methylamide. Yield: 0.52 g (90% of theory); C23H18ClNO2 (M=375.85); calc.: molecular ion peak (M+H)+: 376/378; found: molecular ion peak (M+H)+: 376/378; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: CC(NCC(O)C1C=CC(O)=C(CO)C=1)(C)C.C(C1C=CC=CC=1)(=O)C.Br[CH2:28][C:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])=[O:30].[CH3:41][C:42]([NH:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:44])[CH3:43]>>[CH3:44][C:42]([N:45]([CH2:28][C:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])=[O:30])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:41])[CH3:43]
Reactant: O=C(CBr)OC(=O)c1ccccc1O
Reactant: CC(C)(C)NCc1ccccc1
Agent: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Solvent: CC(=O)c1ccccc1
Product: CC(C)(C)N(CC(=O)OC(=O)c1ccccc1O)Cc1ccccc1

Procedure:
Albuterol has been prepared, see Irish Patent Specification No. 31391, Aug. 9, 1972, starting from the appropriate acetophenone derivative methyl-5-(bromoacetyl-2-hydroxybenzoate, by condensation with N-(1,1-dimethylethyl)benzenemethanamine in the presence of base to form the ketonic ester, methyl-5[[(1,1-dimethylethyl)(phenylmethyl)-amino]acetyl-2-hydroxybenzoate. The ketonic ester is reduced with lithium aluminum hydride in tetrahydrofuran under nitrogen to yield α1-[[(1,1-dimethylethyl)-(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol which is subsequently debenzylated with hydrogen in the presence of palladium on carbon catalyst to produce albuterol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:14]([O:16][CH3:17])=[O:15])#[C:10][C:11]([O-:13])=[O:12].[CH3:18]O>>[CH3:17][O:16][C:14](=[O:15])[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C#CC(=O)[O-]
Product: COC(=O)C=C(Nc1ccc(F)cc1)C(=O)OC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
50 ml (0.51 M) of 4-fluoroaniline (at 98%) are introduced into 500 ml of anhydrous methanol, followed by dropwise addition of 70.5 ml (0.56 M) of methyl acetylenedicarboxylate (at 98%). The reaction mixture is heated at 55° C. with stirring for 3 hours, and then evaporated under reduced pressure. The residue is purified by evolution through silica.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CN(C)C=O>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(O)CO
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
83 g (0.5 mol) of 3-methylxanthine are dissolved in 1250 ml of dimethylformamide, and 12 g (0.5 mol) of sodium hydride are added in portions at room temperature, while stirring. Stirring is continued for 30 minutes, after which 55.3 g (0.5 mol) of 1-chloro-2,3-propanediol in 100 ml of dimethylformamide are added dropwise and the mixture is heated for 18 hours at 110° C., while stirring. Working up is carried out as described in Example 55a).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]#[CH:25])[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N+:27]=[N-:28].CN(C=O)C>>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]5[N:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[N:27]=[N:28][CH:25]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OCc2cnnn2-c2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 110 °C
Yield: 13.9 %

Procedure:
In a 5 mL microwave vial, was added 2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Example 9A, 27 mgs, 0.076 mmol), azidobenzene (Example 9B, 30 mgs, 0.252 mmol), anhydrous DMF (2.5 mL, 32.3 mmol) and (Cp*RuCl)4 (12 mgs) under a nitrogen atmosphere. The vial was capped and heated at 110° C. for 20 min. in the microwave apparatus. The solvent was evaporated and the residue was purified by silica gel chromatography ISCO, concentrated and twice triturated with methanol (2×1 mL). To the solid was added acetonitrile (2 mL) and water (4 mL) and the mixture was freeze dried over the weekend to give the title material (5 mgs, 10.54 μmol, 14% yield). LC (Method F): 2.480 min. HRMS (ESI) calcd for C23H19N6O4S [M+H]+ m/z 475.1183. found 475.1234. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.35 (s, 1H), 8.12 (s, 1H), 7.66-7.73 (m, 2H), 7.53-7.63 (m, 3H), 6.84 (dd, J=2.0, 0.8 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 5.40 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17](/[CH:21]=[CH:22]/[C:23]3[C:24]4[C:29]([N:30]=[C:31]5[C:36]=3[CH:35]=[CH:34][CH:33]=[CH:32]5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[CH3:37][I:38]>C(#N)C>[I-:38].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17](/[CH:21]=[CH:22]/[C:23]3[C:36]4[C:31]([N+:30]([CH3:37])=[C:29]5[C:24]=3[CH:25]=[CH:26][CH:27]=[CH:28]5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CI
Reactant: COCCOCCn1c2ccccc2c2cc(/C=C/c3c4ccccc4nc4ccccc34)ccc21
Solvent: CC#N
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3c4ccccc4[n+](C)c4ccccc34)ccc21
Product: [I-]
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 12 (0.20 g, 0.4 mmol) and methyl iodide (0.57 g, 4 mmol) in acetonitrile (8 mL) was heated to 100° C. in sealed tube for 24 h. After cooling down to room temperature, the solvent was removed and the resulting mixture was purified by precipitation from methanol and ethyl acetate to afford SAM (0.15 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=8.0 Hz, 2H), 8.49 (s, 1H), 8.46 (d, J=8.8 Hz, 2H), 8.31 (d, J=16 Hz, 1H), 8.26 (t, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.83 (t, J=7.2 Hz, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.46 (t, J=6.4 Hz, 2H), 7.44 (d, J=16 Hz, 1H), 7.20 (t, J=6.4 Hz, 1H), 4.82 (s, 3H), 4.46 (t, J=6.0 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 3.55-3.53 (m, 2H), 3.44-3.42 (m, 2H), 3.30 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 157.9, 149.5, 141.8, 140.5, 140.1, 137.8, 129.3, 127.4, 126.9, 126.5, 126.2, 123.9, 123.2, 122.1, 121.2, 121.1, 119.9, 117.9, 117.4, 109.4, 109.0, 71.7, 70.6, 69.0, 58.9, 43.3, 39.5. HRMS (MALDI-TOF) m/z Calcd for C33H31N2O2+ 487.2380 Found 487.2387 [M]+.
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH:11]=[C:12]([O:15][C@H:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@@H:19]([NH2:26])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:26][C@@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:7][N:8]=4)[CH:11]=3)[CH2:17][CH2:18]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of Intermediate 75b (62.0 mg, 0.18 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 78.9 mg, 0.195 mmol), DIPEA (46.3 μL, 0.27 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (22 mg, 20%). LCMS (Method 5) Rt 4.30 min, nth 605 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.79-2.15 (8H, m), 2.36 (3H, s), 3.49 (4H, m), 4.81 (1H, m), 5.51 (1H, t, J 4.5), 6.30 (1H, s), 7.03 (1H, dd, J 10.1, 2.2), 7.09 (1H, d, J 8.5), 7.25-7.40 (8H, m), 7.51 (1H, m), 7.83 (1H, m), 8.07 (1H, s).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]#[N:11])=[N:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)nc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C=O)cn1
Temperature: 120 °C
Yield: 57.4 %

Procedure:
A mixture of 6-bromonicotinaldehyde (11.2 g, 60 mmol) and CuCN (8.06 g, 90 mmol) in DMF (100 mL) was heated at 120° C. for 3 h under N2. The mixture was cooled to rt and diluted with EtOAc and filtered through a pad of celite. The organic layer was washed with water and brine and then dried (MgSO4) and concentrated. The product 5-formylpicolinonitrile (4.55 g) was obtained by silica gel chromatography (elution with 0-20% EtOAc/Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccccc1OCc1cccc(OCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.7 %

Procedure:
A solution of 215 mg of 1-[(2-chlorophenoxy)methyl]-3-[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]benzene, as prepared in the preceding step, in methylene chloride (2 mL) was treated with 1.5 mL of 4 N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to provide 183 mg of the title compound as a colorless powder after repeated concentrations from diethyl ether/hexane/methanol. 1H-NMR (300 MHz, DMSO-d6) δ 8.51 (br s, 2 H), 7.45 (dd, 1 H, J=1.3, 7.9 Hz), 7.27-7.35 (m, 2 H), 7.21 (d, 1 H), 6.90-7.05 (m, 4 H), 5.18 (s, 2 H), 3.87 (d, 2 H), 2.90 (t, 2 H, J=10 Hz), 2.05 (m, 1 H), 1.91 (d, 2 H, J=13.8 Hz), and 1.5-1.54 (m, 2 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H22ClNO2: 332.1 (M+H). Found: 332.0.
Reaction SMILES: [C:1]([N:4]1[C:8]([NH2:9])=[N:7][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5]1)(=[O:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34]([NH:9][C:8]1[N:4]([C:1](=[O:3])[CH3:2])[N:5]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:7]=1)=[O:35])[CH3:22]
Reactant: CCCCCCCCCCCc1nc(N)n(C(C)=O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCCCCc1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(C(C)=O)n1
Temperature: 20 °C
Yield: 66.3 %

Procedure:
A slurry of 1-acetyl-5-amino-3-undecyl-1,2,4-triazole (3.56 g, 12.7 mmol) was warmed until homogeneous. 2,6-Diisopropylphenyl isocyanate (2.71 mL, 12.7 mmol) was added and the resulting solution was heated under reflux for 15 hours. The resulting solution was cooled (20° C.) and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and the resulting oil was chromatographed on silica (85:15 hexane:ethyl acetate) to yield 4.07 g (66.3%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]([NH:10][C:11](=[N:14][CH3:15])SC)#[N:9]>N1C=CC=CC=1>[C:8]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])=[N:14][CH3:15])#[N:9]
Reactant: NCCCCCO
Reactant: CN=C(NC#N)SC
Solvent: c1ccncc1
Product: CN=C(NC#N)NCCCCCO
Yield: 44 %

Procedure:
A mixture of 5-aminopentan-1-ol (20 g.) and N-cyano-N',S-dimethylisothiourea (25 g.) in pyridine (130 ml) was heated on a steam-bath for 14 hours, evaporated to dryness, and the residue recrystallised from chloroform/methanol to give N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (15.7 g). A recrystallised sample had m.p. 116°-119°.
Reaction SMILES: C[Si](CCOC[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)(C)C.FC(F)(F)S(O[CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=O)=O>C(Cl)Cl>[N:9]1[CH:10]=[CH:11][C:12]([O:15][CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)cc1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(Oc1ccncc1)C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of benzyl lactate (6.0 g, 33 mmol) and N-methyl morpholine (2.7 mL, 33 mmol) in 100 mL of anhydrous methylene chloride at −20° C. was added trifluoromethanesulfonyl anhydride (5.6 mL, 33 mmol). After stirring at −20° C. for 1 h, the reaction mixture was diluted with 100 mL of hexane and washed with dilute aqueous sodium hydrogen sulfate and brine/saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% ether in hexane to give benzyl 2-trifluoromethanesulfonyloxypropionate (6.4 g), which was used immediately for the ensuing reaction. Thus, a mixture of N-trimethylsilylethoxymethyl-4-pyridone (Step A, 3.4 g, 15 mmol) and benzyl 2-trifluromethanesulfonyloxypropionate (4.7 g, 15 mmol) was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was dissolved in methylene chloride and loaded onto a silica gel column, which was eluted with 5% methanol in methylene chloride to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.57 (d, 2H), 7.42 (d, 2H), 7.4-7.3 (n, 5H), 5.44 (q, 1H), 5.24 (ABq, 2H), 1.72 (d, 3H). LC-MS: m/e 258 (M+H)+ (1.8 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:22]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCl
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
A solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (6.1 g, 0.023 mole), 1-chlorobutane (2.42 g, 0.026 mole), K2CO3 (10 g) and KI (0.1 g) in 100 ml dimethylformamide was heated at 70° C. for a total of 7 hours.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]1.[Cl:25]CCl>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:22]([CH2:23][CH:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:10])[CH2:18][C:19]([OH:21])=[O:20])[NH:9][C:4]=2[CH:3]=1.[ClH:25]
Reactant: ClCCl
Reactant: Cc1ccccc1C1CC(=O)OC(=O)C1
Reactant: Nc1ccc(I)cc1N
Product: Cc1ccccc1C(CC(=O)O)Cc1nc2ccc(I)cc2[nH]1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 4-iodo-1,2-phenylenediamine (0.47 g) in dichloromethane (3 ml) the solution of 3-(2-methylphenyl)glutaric anhydride (0.41 g) in dichloromethane (4 ml) was added with stirring at rt. Almost instantaneously an resinous precipitate is formed. After 1 h at rt all volatiles are removed in vacuo and the residue is taken up in 1,4-dioxane (2 ml). 4M HCl in 1,4-dioxane (3 ml) is added and the resulting dark solution is heated to reflux for 1 h. Again all volatiles are removed at the water aspirator and the residue is recrystallised from EtOAc/methanol to give 4-(5-iodo-2-benzimidazolyl)-3-(2-methylphenyl)butanoic acid•HCl (0.49 g) as light brown solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: C#CCCO
Reactant: Brc1cncc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine)palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline, 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.