Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[I-].[Na+].C(=O)(O)[O-].[Na+].[CH3:29][C:30]([S:33]([CH2:36][CH2:37][Cl:38])(=[O:35])=[O:34])([CH3:32])[CH3:31]>CN(C=O)C.CO>[ClH:38].[ClH:38].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:37][CH2:36][S:33]([C:30]([CH3:32])([CH3:31])[CH3:29])(=[O:35])=[O:34])[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)S(=O)(=O)CCCl
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1cc(OC2CCN(CCS(=O)(=O)C(C)(C)C)CC2)c2ncccc2c1
Product: Cl
Temperature: 150 °C
Yield: 7.1 %

Procedure:
A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (37 mg, 0.25 mmol), sodium bicarbonate (168 mg, 2.0 mmol) and 2-chloroethyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 12) (208 mg, 1.1 mmol) in DMF (2 ml) was heated at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (20 g) preconditioned with methanol and was eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue (118 mg) was purified by MDAP (×2). Appropriate fractions were combined and concentrated in vacuo to give the free base of the title compound (10 mg, 8%): This was diluted with methanol and treated with 1.25 M hydrogen chloride solution in methanol (0.05 ml) and the solution was evaporated in vacuo to give the title compound (12 mg): LCMS RT=2.73 min, ES+ve m/z 433 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([OH:27])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH:39]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](Cl)=[O:51])=[CH:45][CH:44]=1)([CH3:41])[CH3:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([O:27][C:50](=[O:51])[CH2:49][C:46]2[CH:47]=[CH:48][C:43]([O:42][CH:39]([CH3:40])[CH3:41])=[CH:44][CH:45]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)CCCCCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)Oc1ccc(CC(=O)Oc2cc(C(=O)CNC(C)(C)C)ccc2OC(=O)CCCCCC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with p-isopropoxyphenylacetyl chloride there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][Si:4](OCC)(OCC)[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:28]2[CH:33]=[CH:32][C:31]([Si:34](OCC)(OCC)[O:35][CH2:36][CH3:37])=[CH:30][CH:29]=2)[C:12]2[CH:17]=[CH:16][C:15]([Si:18](OCC)(OCC)[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:50]([Mg]Br)[CH:51]=[CH2:52].Cl>CCOCC>[CH2:50]([CH:37]([CH2:16][CH:15]=[CH2:14])[CH2:36][O:35][SiH2:34][C:31]1[CH:32]=[CH:33][C:28]([N:11]([C:12]2[CH:13]=[CH:14][C:15]([SiH2:18][O:19][CH2:20][CH:21]([CH2:10][CH:5]=[CH2:6])[CH2:17][CH:12]=[CH2:13])=[CH:16][CH:17]=2)[C:8]2[CH:9]=[CH:10][C:5]([SiH2:4][O:3][CH2:1][CH:2]([CH2:33][CH:28]=[CH2:29])[CH2:9][CH:8]=[CH2:7])=[CH:6][CH:7]=2)=[CH:29][CH:30]=1)[CH:51]=[CH2:52]
Reactant: C=CC[Mg]Br
Reactant: CCO[Si](OCC)(OCC)c1ccc(N(c2ccc([Si](OCC)(OCC)OCC)cc2)c2ccc([Si](OCC)(OCC)OCC)cc2)cc1
Agent: Cl
Solvent: CCOCC
Product: C=CCC(CC=C)CO[SiH2]c1ccc(N(c2ccc([SiH2]OCC(CC=C)CC=C)cc2)c2ccc([SiH2]OCC(CC=C)CC=C)cc2)cc1
Yield: 34 %

Procedure:
Firstly, dist. ether (5 mL) was added to tris(4-triethoxysilylphenyl)amine (242 mg, 0.33 mmol) under a nitrogen atmosphere. Then, 1-M allylmagnesium bromide (4 mL (solvent: ether), 4 mmoL) was added dropwise at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at room temperature for 20 hours to obtain a mixture. Subsequently, the mixture was added with an aqueous solution of HCl of 10% by mass to cease the reaction, and the pH of an aqueous layer was adjusted to 4 by using an aqueous solution of HCl of 10% by mass. After that, an organic layer was separated, and the aqueous layer was extracted with ether. The organic layer thus collected was washed with sat. NaHCO3 and sat. NaCl, and was dried with MgSO4. The dried organic layer was then filtered and concentrated to obtain a crude product. Subsequently, the crude product was separated and purified by PTLC (hexane/EtOAc=10/1) to obtain tris(4-diallylethoxysilylphenyl)amine (80 mg, 34% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:32](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:25]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=[N:27][N:28]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A mixture of 7.5 g of 4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 5.17 g trityl chloride and 1.92 g triethylamine in 50 mL CH2Cl2 is stirred overnight. After water addition and acidification with 1N HCl to pH 3, the mixture was separated and the organic phase was extracted with CH2Cl2/ ethyl acetate (1:1). The mixture was dried with Na2SO4, suction filtered and the solvent evaporated. 6.46 g of product was obtained after flash chromatography with ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[N:3]=1.[CH3:18][N:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:21]([CH3:34])[C:20]1=[O:35]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:23]3[CH:22]=[C:21]([CH3:34])[C:20](=[O:35])[N:19]([CH3:18])[CH:24]=3)=[N:3][C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Product: Cc1cc(-c2nc(CS(C)(=O)=O)ncc2OCC2CC2)cn(C)c1=O

Procedure:
The title compound of Example 143, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.67 (s, 3H), 3.11 (s, 3H), 2.24 (s, 3H), 1.29-1.27 (m, 1H), 0.72-0.67 (m, 2H), 0.39-0.35 (m, 2H). LCMS: 364.1 (M+1)+
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[N:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:4][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[CH:19]=2)[CH:7]=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(-c3cnn(C(C)(C)C)c3)cc3ncccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)n1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylate (2.24 g, 4.64 mmol) in DCM (14 ml) was added TFA (8.22 ml, 107 mmol) and this was stirred at ambient temperature for 2 h. After this time the reaction had gone to completion and so was concentrated in vacuo to yield the crude product. This was dissolved in methanol and loaded onto an SCX cartridge (50 g). It was eluted with methanol (3 CVs) and product eluted as the free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow foam (1.55 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)[C:12](F)=[N:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:17]=2)[C:12]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3NC3CCOCC3)n2)cc1
Temperature: 120 °C
Yield: 74.4 %

Procedure:
A mixture of tetrahydro-2H-pyran-4-amine (130 mg, 1.285 mmol), 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (345 mg, 0.719 mmol), and cesium carbonate (165 mg, 0.506 mmol) in THF (2.5 mL) was heated under microwave irradiation (100° C., 15 min; 120° C., 2×15 min). The mixture was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with water, saturated NH4Cl, dried over Na2SO4 and concentrated. The resulting solid was triturated with hot MeOH (10 mL) to give a yellow solid (300 mg). LCMS (ES, pos.): calcd for C30H33ClN6O3: 560.2. found: 561.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.48 (d, J=7.24 Hz, 1H); 8.67 (d, J=2.54 Hz, 1H); 8.13 (d, J=2.54 Hz, 1H); 7.18 (t, J=9.10 Hz, 4H); 6.87 (d, J=8.61 Hz, 4H); 4.82 (s, 2H); 4.77 (s, 2H); 4.17-4.29 (m, 1H); 3.91 (dt, J=11.74, 3.62 Hz, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.55 (td, J=11.25, 1.96 Hz, 2H); 2.52 (s, 3H); 1.96 (br. s., 2H); 1.33-1.48 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42]>C(#N)C>[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: CN1CCCC1CCN
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/C=C(/CNCCC2CCCN2C)COc2cccc3ccccc23)cc1
Yield: 48 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved acetonitrile (5 ml) in a 100 ml vessel at 0° C., and thereto triethylamine (0.21 ml, 1.5 mmol, 1.5 eq.) and 2-(1-methylpyrrolidin-2-yl)ethylamine (R1′″NH2; 0.22 ml, 1.5 mmol, 1.5 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the solvent was distilled off, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound as pale yellow oil (yield 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20](O)=O)=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:16]1.C(Cl)(=O)C(Cl)=O.C[N:39](C)[CH:40]=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][C:40]([NH2:39])=[O:41])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:27])[F:28])=[N:16]1
Reactant: CN(C)C=O
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CC(N)=O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.84 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid was dissolved in 10 mL of dichloromethane, and 0.2 mL of oxalyl dichloride and N,N-dimethylformamide in a catalytic amount were added, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the resulting product was dissolved in 10 mL of tetrahydrofuran, and the solution was dropwise added to a mixed solution comprising 30 mL of a 25 mass % ammonia water and 40 mL of tetrahydrofuran at −30° C. Then, stirring was carried out for 12 hours while the temperature was slowly increased to room temperature. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.80 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxyamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:23])(C)(C)C.CC([O-])(C)C.[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:27]3[CH:28]=[CH:29][C:24]([C@@H:22]([NH2:21])[CH3:23])=[CH:25][CH:26]=3)[CH2:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(OC2CNC2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To 5.0 g (21.8 mmol) 3-(4-ethoxy-phenoxy)-azetidine and 6.5 g (21.8 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) in 80 mL 1,4-dioxane under an argon atmosphere are added 8.6 g (87.1 mmol) KOtBu, 0.65 g (2.18 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.0 g (1.09 mmol) tris-(dibenzylideneacetone)-dipalladium(0). The mixture is stirred for 2 h at 120° C. Subsequently 200 mL MeOH and 5 mL water are added and the mixture is filtered and concentrated in vacuo. The residue is taken up in ethyl acetate and is washed with water. The organic layer is concentrated and the residue is purified by HPLC (eluent A: water+0.1% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:17]NC(=O)CCC(N)=O>CN(C=O)C>[Br:17][C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[N:10]2[CH:11]=1
Reactant: CCCN(CCC)c1cccc2nccn12
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Product: CCCN(CCC)c1cccc2nc(Br)cn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
N,N-Dipropylimidazo[1,2-a]pyridin-5-amine (1.0 g, 4.6 mmol) was diluted in DMF (25 mL). The solution was cooled to 0° C. N-bromosuccinamide (0.83 g, 4.7 mmol) was added. After 5 minutes, the reaction was quenched with water. The solution was extracted with ether, dried, and concentrated. Flash chromatography (40% EtOAc/hexanes) gave the title compound as a yellow oil which solidified upon overnight freezing at −20° C. 0.67 g obtained (49% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1Cc1ccccc1

Procedure:
A solution of 2-[4-benzyloxy-2-(hydroxy-phenyl-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester (1.67 g, 3.97 mmol maximum) in ethanol (50 mL) was treated with 5% Pd/C (0.42 g) and hydrogen (60 psi, rt, 18 h). The mixture was filtered and concentrated to a viscous colorless oil (1.15 g, 91%): 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 3.99 (s, 2H), 4.30 (q, 2H, J=7.0 Hz), 4.93 (brs, 1H), 6.58-6.66 (m, 3H), 7.22-7.34 (m, 5H); MS (ES) m/e 315 [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCOC(C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 36.4 %

Procedure:
Dissolve 3-nitro-5-(trifluoromethyl)aniline (300 mg, 1.45 mmol) in DCM (5 mL), add triethylamine (294 mg, 2.9 mmol) and then methylsulfonyl chloride (182 mg, 1.6 mmol). Stir the reaction at room temperature for 17 hrs. TLC (EtOAc:PE=1:3) shows the reaction is complete. Concentrate under reduced pressure to afford the crude product. Purification by chromatography (silica gel, EtOAc:PE=3:7) affords the title compound (150 mg, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][CH:15]([CH2:25][C:26]#[C:27][CH3:28])[CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[Cl:38][C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1>[ClH:24].[CH2:25]([CH:15]1[CH2:16][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:39](=[O:41])[N:14]1[CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=2)[CH:9]=[N:10][CH:11]=1)[C:26]#[C:27][CH3:28].[ClH:38]
Reactant: CC#CCC(CNc1cccc(Cl)c1)NCc1cncn1Cc1ccc(C#N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CCC1CN(c2cccc(Cl)c2)C(=O)N1Cc1cncn1Cc1ccc(C#N)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step M (75 mg, 0.14 mmol) in 1.0 mL of THF at 0° C. was added triethylamine (0.12 mL, 0.89 mmol), followed by triphosgene (26 mg, 0.088 mmol). The reaction was stirred at 0° C. for two hours, then poured into EtOAc and washed with sat. aq. NaHCO3 and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by silica gel chromatography (50-75% acetone/hexane), taken up in CH2Cl2 and treated with 1M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride (14 mg) was isolated as an orange powder.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24](=[O:43])[C@@H:25]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:26]([CH3:34])[CH2:27][CH:28]([CH3:33])[CH2:29][CH2:30]C=C)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:38]([O:37][C:36](=[O:42])[NH:35][C@@H:25]1[C:24](=[O:43])[N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@H:18]2[C:16](=[O:17])[NH:15][C@:10]2([C:8](=[O:9])[NH:7][S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:6])=[O:5])[CH2:12][C@H:11]2[CH:13]=[CH:14][CH2:30][CH2:29][CH:28]([CH3:33])[CH2:27][C@H:26]1[CH3:34])([CH3:41])([CH3:39])[CH3:40]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (9.5 g, 15.21 mmol) in DCE (2500 ml) was sparged with nitrogen for 30 min. and then Hoveyda-Grubbs Catalyst 2nd Generation (0.574 g, 0.912 mmol) was added and the reaction heated to 80° C. for 2 hrs then cooled down to 45° C. and stirred for 2 days. The reaction was concentrated and purified by flash chromatography on silica gel (20-60% Acetone in hexanes) to give the product tert-Butyl((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (7 g). MS: MS m/z 597.35 (M++1).