Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[C-:24]#[N:25].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[N:5]=[C:6]([C:24]#[N:25])[N:7]=1
Reactant: [C-]#N
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Agent: [K+]
Solvent: CC#N
Product: CC(C)Nc1nc(C#N)nc(Cl)c1-c1c(F)cccc1Cl
Yield: 71.3 %

Procedure:
A solution of 1.0 g (2.63 mmol) of sulfone 3 and 0.21 g (3.16 mmol) of potassium cyanide in acetonitrile was stirred at 20-25° C. for 5 days. The solvent was distilled off and the residue was digested with MTBE:ethyl acetate [EA] 9:1. Filtration and concentration of the filtrate gave 0.61 g of the title compound of m.p 186-188° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=2)[N:15]1[CH2:28][C:29](O)=[O:30]>>[Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:29](=[O:30])[CH2:28][N:15]2[C:16]3[C:21](=[CH:20][C:19]([C:24]([F:25])([F:27])[F:26])=[CH:18][CH:17]=3)[CH:22]=[CH:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Yield: 55 %

Procedure:
The title compound was prepared from 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (502 mg, 2.50 mmol) and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (675 mg, 2.49 mmol) using protocol A (626 mg, 55% yield). Method [7] Retention time 5.59 min by HPLC (M+=454 and 456) and (M+Na=476 and 478). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.38 (broad s, 1H), 8.27 (s, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3, 1H), 7.17 (s, 1H), 6.87 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[CH:25][N:24]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[CH:31]1([CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([C:2]3[O:1][C:5]4[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:8]=[CH:9][C:4]=4[N:3]=3)=[N:24][CH:25]=2)[CH2:32][CH2:33]1
Reactant: Brc1ccc(OCC2CC2)cn1
Reactant: C[C@@H](COc1ccc2ncoc2c1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)cn3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 125 °C
Reaction time: 15 h
Yield: 47.6 %

Procedure:
A mixture of tert-butyl ((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)carbamate (516 mg), 2-bromo-5-(cyclopropylmethoxy)pyridine (604 mg), palladium(II) acetate (19.8 mg), butyldi(1-adamantyl)phosphine (63.3 mg), tripotassium phosphate (749 mg) and N-methylpyrrolidone (7 mL) was stirred at 125° C. for 15 hr under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (369 mg).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(=O)C>>[CH3:1][N:2]([CH:3]1[CH2:16][CH:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH2:14]2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: CC(=O)Cl
Product: CC1C2CCC3C4CCC5CC(N(C)C(=O)c6ccccc6)CCC5(C)C4CCC32CN1C

Procedure:
The title compound was prepared according to procedures described in Example 7C, except substituting Compound 172B for Compound 7B and benzoyl chloride for acetyl chloride. 1H NMR (CDCl3): δ 0.75 (s, 3 H) 0.85-2.00 (m, 26 H) 2.21 (m, 3 H) 2.80 (s, 3 H) 2.98 (s, 3 H) 3.46 (m, 1 H) 7.39 (m, 5 H); (M+H)+=449.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[CH:9][CH:8]=1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:34]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:35])[CH:16]=[CH:15][C:14]=2[Cl:20])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester hydrochloride (521 mg), triethylamine (0.49 ml) and cyclohexanecarbonyl chloride (0.26 ml) in dry THF (25 ml) was stirred at 20 C for 18 h. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure to give the product (714 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:12]([CH3:14])=[CH2:11])=[C:4]([F:9])[CH:3]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)COc1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 4-bromo-2-fluorophenol (26.8 g) and 3-chloro-2-methylprop-1-ene (13.7 mL) in acetone (420 mL) was added potassium carbonate (29 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (29.9 g, 87%).
Reaction SMILES: N1C(C)=CC=[CH:3][C:2]=1C.C(Cl)(=O)C(Cl)=O.CNC(=O)C.[OH:20][C:21]([CH3:49])([CH3:48])[CH2:22][C@@:23]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]2[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=[O:37])=[CH:34][CH:33]=2)[CH3:31])[CH2:25][CH2:24]1>ClCCl>[OH:20][C:21]([CH3:48])([CH3:49])[CH2:22][C@@:23]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]2[CH:41]=[CH:40][C:35]([C:36]3[O:37][C:2]([CH3:3])=[N:39][N:38]=3)=[CH:34][CH:33]=2)[CH3:31])[CH2:25][CH2:24]1
Reactant: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CNC(C)=O
Product: Cc1nnc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,6-Lutidine (88 μL) followed by oxalyl chloride (32 μL) was added to a solution of N-methyl-acetamide (28 mg) in dichloromethane (3 mL) chilled in an ice bath. After stirring the solution for 15 min, 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid hydrazide (154 mg) was added and then the cooling bath was removed. The solution was stirred for 1 h and then neutralized by the addition of saturated aqueous NaHCO3 solution. The resulting mixture was extracted twice with dichloromethane and the combined extracts were dried (MgSO4) and concentrated. The residue was taken up in acetic acid (1 mL) and stirred at 120° C. for 2.5 h. After cooling to ambient temperature, the solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->95:5) to afford pure Example 3 and a mixture containing Example 2. Example 2 was separated by a second chromatography on silica gel (CH2Cl2/MeOH 92:8).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([N:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C=O.[C:32](OC(OC(=O)C)(OC(=O)C)C(O[BH3-])=O)(=O)C.[Na+]>ClCCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([N:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:15][CH2:14][N:13]([CH3:32])[CH2:12][CH2:11]1)=[O:9]
Reactant: [BH3-]OC(=O)C(OC(C)=O)(OC(C)=O)OC(C)=O
Reactant: Cc1cc(F)ccc1[C@H]1CCNCCN1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(F)ccc1[C@H]1CCN(C)CCN1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Yield: 20.6 %

Procedure:
A mixture of example 6 (51 mg), aqueous formaldehyde (33 μL) and sodium triacetoxyacetoxyborohydride (50 mg) in anhydrous 1,2-dichloroethane (2 mL) was stirred at r.t. overnight. The mixture was washed with water (2 mL) and brine (2 mL) and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt 100%) to give 7-(R)-(4-fluoro-2-methyl-phenyl)-4-methyl-[1,4]-diazepane-1-carboxylic acid, (3,5-dichloro-benzyl)-methylamide (10 mg).
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14]C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1>CN1CCCC1=O.O>[C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(C)=O)c2sc(=O)[nH]c12
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 7-acetyl4-methoxy-1,3-benzothiazol-2(3H)-one (1.2 g), pyridine hydrochloride (2.77 g), in dry 1-methyl-2-pyrrolidone(6 ml), was heated at 190° C. in a microwave reactor for 90 min. The reaction mixture was cooled to room temperature, and diluted with water. The precipitated solid was collected by filtration, washed with water and dried under vacuum at 40° C. to give the title compound (1.07 g). LCMS RT=2.46 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2cccs2)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.34–7.38 (m, 1H), 7.24–7.26 (m, 1H), 7.12 (s, 1H), 7.04–7.08 (dd, 1H), 6.96–7.2 (m, 2H), 6.88–6.94 (m, 2H), 4.32–4.42 (q, 2H), 3.52–3.58 (m, 4H), 3.05–3.35 (m, 4H), 1.32–1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164.2, 128, 126.8, 126.6, 120.2, 118.4, 115.2, 62.5, 54.2, 50.5, 42.6,44, 14.6.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[N:42]([CH3:43])[C:41](=[O:44])[C@H:40]([C@H:45]([OH:47])[CH3:46])[NH:39][C:38](=[O:48])[C@H:37]([C@H:49]([OH:56])[C@H:50]([CH3:55])[CH2:51][CH2:52][CH2:53][CH3:54])[N:36]([CH3:57])[C:35](=[O:58])[C@H:34]([CH:59]([CH3:61])[CH3:60])[N:33]([CH3:62])[C:32](=[O:63])[C@H:31]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:30][C:29](=[O:68])[C@H:28]([CH2:69][CH:70]([CH3:72])[CH3:71])[N:27]([CH3:73])[C:26](=[O:74])[C@@H:25]([CH3:75])[NH:24][C:23](=[O:76])[C@H:22]([CH3:77])[NH:21][C:20](=[O:78])[C@H:19]([CH2:79][CH:80]([CH3:82])[CH3:81])[N:18]([CH3:83])[C:17](=[O:84])[C@H:16]([CH2:85][CH:86]([CH3:88])[CH3:87])[NH:15][C:14](=[O:89])[C@H:13]([CH2:90][CH:91]([CH3:93])[CH3:92])[N:12]([CH3:94])[C:11]1=[O:95])C1C=CC=CC=1>CO.[Pd]>[OH:47][C@@H:45]([C@@H:40]1[NH:39][C:38](=[O:48])[C@H:37]([C@H:49]([OH:56])[C@H:50]([CH3:55])[CH2:51][CH2:52][CH2:53][CH3:54])[N:36]([CH3:57])[C:35](=[O:58])[C@H:34]([CH:59]([CH3:60])[CH3:61])[N:33]([CH3:62])[C:32](=[O:63])[C@H:31]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:30][C:29](=[O:68])[C@H:28]([CH2:69][CH:70]([CH3:71])[CH3:72])[N:27]([CH3:73])[C:26](=[O:74])[C@@H:25]([CH3:75])[NH:24][C:23](=[O:76])[C@H:22]([CH3:77])[NH:21][C:20](=[O:78])[C@H:19]([CH2:79][CH:80]([CH3:81])[CH3:82])[N:18]([CH3:83])[C:17](=[O:84])[C@H:16]([CH2:85][CH:86]([CH3:88])[CH3:87])[NH:15][C:14](=[O:89])[C@H:13]([CH2:90][CH:91]([CH3:93])[CH3:92])[N:12]([CH3:94])[C:11](=[O:95])[C@@H:10]([CH2:9][OH:8])[N:42]([CH3:43])[C:41]1=[O:44])[CH3:46]
Reactant: CCCC[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)[C@H](COCc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)[C@H](CO)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-3-[(Benzyloxy)methyl]-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30,33-pentaisobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (22 mg) are dissolved in MeOH (1 ml) and hydrogenated at room temperature and atmospheric pressure over 5% Pd on charcoal. After 2 hrs, the catalyst was filtered off and the filtrate was concentrated in vacuo under reduced pressure. The residue was purified by silica-gel column chromatography (hexane-acetone, 1:1) to yield (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxymethyl)-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30,33-pentaisobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (18 mg).
Reaction SMILES: [N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:11]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C@H:12]([CH3:14])[NH:8][C:7]1[CH:9]=[CH:10][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(N=[N+]=[N-])cc1

Procedure:
Following General Procedure A above and using 4-azidoaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure O above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:25]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[Cl-].[NH4+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]([N:11]([CH3:12])[CH3:13])=[O:10])[C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CN(C)C(=O)C(c1ccc(Br)cc1)C1(O)CCCCC1
Temperature: -78 °C

Procedure:
4-bromo-N,N-dimethylbenzene acetamide (15 g, 0.06 mole) was added to dry T.H.F. (250 ml) and the solution cooled to -78° C. under nitrogen. Straight chain butyl lithium in hexane (43.3 ml, 0.06 mole) was added dropwise, the temperature being maintained below -70° C. throughout. An orange coloured precipitate formed. After addition, the reaction mixture was maintained near -70° C. for 20 minutes and cyclohexanone (7.5 ml, 0.07 mole) was added. After a further 50 minutes at -78° C. the reaction mixture was poured into stirring saturated ammonium chloride solution. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated. The product crystallised and was filtered with isopropanol (9.8 g, m.p. 140 °-144° C.).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:23])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N=C=NCCCN(C)C)C.[N:35]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17]([NH:44][S:41]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:43])=[O:42])=[O:18])=[C:15]([F:23])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CCOCC1)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid (0.17 g, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.22 g, 1.15 mmol) and 4-dimethylaminopyridine (0.14 g, 1.15 mmol) in anhydrous dichloromethane (10 mL) was added morpholine-4-sulfonamide (0.17 g, 1.0 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h. The mixture was quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography using 10-60% gradient ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as an off-white solid (0.05 g, 20%): 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 6.88 (s, 1H), 4.06 (d, J=6.8 Hz, 2H), 3.39 (s, 3H), 2.50-2.42 (m, 1H), 2.12-2.05 (m, 1H), 1.98-1.94 (m, 1H), 1.90-1.68 (m, 4H), 1.50-1.41 (m, 2H), 1.22 (s, 3H), 0.87 (s, 3H); MS (ES−) m/z 397.2, 399.2 (M−1); MS (ES+) m/z 399.1, 401.1 (M+1);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Cl[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1>>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14]1
Reactant: CN1CCCC(CCl)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CN1CCCC(COc2ccc(N)cc2)C1

Procedure:
Using the procedure of Example 56, 4-nitro-phenol Compound 104a was used in place of Compound 36a and 3-chloromethyl-1-methyl-piperidine Compound 104b was used in place of Compound 56a and carried forward to provide 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine Compound 104d. MS 221 (MH+). Using the procedure of Example 1, 5-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 43c was used in place of Compound 1 and Compound 104d was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 32. MS 583, 585, 587 (MH+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:12])(=O)=O>ClCCl>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([Cl:12])[S:2][CH3:1])[CH3:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CSC
Solvent: ClCCl
Product: CCOC(=O)C(Cl)SC
Temperature: 25 °C

Procedure:
To a Stirred Solution of ethyl (methylthio)acetate (10.8 ml) in dichloromethane (300 ml) cooled to −15° C. is added dropwise sulphuryl chloride (8.1 ml). The mixture is allowed to warm to room temperature over two hours and then concentrated under reduced pressure to give crude chloro-methylsulfanyl-acetic acid ethyl ester as a colourless liquid. The product is used in the next step without further purification. 1H NMR (CDCl3) δ ppm: 5.35 (1H, s); 4.25 (2H, m); 2.30 (3H, s); 1.30 (3H, t).
Reaction SMILES: [CH3:1]N(C)C=O.[CH3:6][O:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][S:13][CH2:14][CH2:15][C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)=[CH:10][CH:9]=1.[H-].[Na+].CI>O>[CH3:1][N:20]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:15][CH2:14][S:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CSCCc2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(CSCCc2nccn2C)cc1
Reaction time: 0.17 h

Procedure:
To a dimethylformamide (15 ml) solution of 2-[2-(p-methoxybenzylthio)ethyl]imidazole (1.5 g) was added 60% sodium hydride (0.29 g) in mineral oil at 0° C. To the mixture was added, 15 minutes later, methyl iodide (0.41 ml) at -20° C., followed by stirring for 10 minutes. The reaction mixture was poured into water (60 ml), which was subjected to extraction with methylene chloride (20 ml×three times). The organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to a silica gel chromatography (3 cm×15 cm), eluting with methanol-methylene chloride (5:95). The desired fraction was concentrated under reduced pressure to afford 1-methyl-2-[2-(p-methoxybenzylthio)ethyl]imidazole (1.6 g) as a colorless oily product.
Reaction SMILES: COC(=O)CC[S:6][C:7]1[CH:8]=[C:9]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:18]=2)=[N:11][CH:12]=1.Cl[C:41]1[CH:46]=[CH:45][N:44]=[C:43]2[CH:47]=[CH:48][S:49][C:42]=12.CC([O-])(C)C.[K+].[NH4+].[Cl-]>CS(C)=O>[O:32]([C:9]1[C:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:18]=2)=[N:11][CH:12]=[C:7]([S:6][C:41]2[CH:46]=[CH:45][N:44]=[C:43]3[CH:47]=[CH:48][S:49][C:42]=23)[CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Reactant: Clc1ccnc2ccsc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 25 mL round-bottomed flask was charged with tert-butyl 4-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (500 mg, 0.876 mmol), 7-chlorothieno[3,2-b]pyridine (178 mg, 1.05 mmol), and DMSO (8 mL). Nitrogen was bubbled through the solution for 10 minutes. Potassium 2-methylpropan-2-olate (295 mg, 2.63 mmol) was added and stirred at room temperature for 30 minutes. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc (2×20 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica (50% EtOAc in hexanes) to afford tert-butyl 4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.