Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:37]1[CH:38]=[CH:39][C:40]3[N:44]=[C:43]([C@@H:45]4[CH2:49][CH2:48][CH2:47][N:46]4[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[NH:42][C:41]=3[CH:61]=1)=[CH:31][CH:30]=2)=O)(C)(C)C.Cl.[CH3:63][O:64][C:65]([NH:67][C@@H:68]([CH:72]([CH3:74])[CH3:73])[C:69](O)=[O:70])=[O:66].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:59][O:58][C:56]([NH:55][C@@H:51]([CH:52]([CH3:53])[CH3:54])[C:50]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[CH:61]=[C:37]([C:32]3[CH:33]=[C:34]4[CH2:35][O:36][C:23]5[CH:22]=[C:21]6[C:26]([CH:27]=[CH:28][C:18]7[N:17]=[C:16]([C@@H:9]8[CH2:10][C@H:11]([CH2:13][O:14][CH3:15])[CH2:12][N:8]8[C@@:68]([NH:67][C:65](=[O:66])[O:64][CH3:63])([CH:72]([CH3:74])[CH3:73])[CH:69]=[O:70])[NH:20][C:19]=76)=[CH:25][C:24]=5[C:29]4=[CH:30][CH:31]=3)[CH:38]=[CH:39][C:40]=2[N:44]=1)=[O:60])=[O:57]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3ccc4nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c4c3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3ccc4nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c4c3)ccc2-5)N([C@@](C=O)(NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A solution of (2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60° C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to 68 mg (0.09 mmol) of this material was added a solution of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (21 mg, 0.12 mmol) and HATU (41 mg, 0.1 mmol) in DMF (1 mL). To the resulting solution was added diisopropylethylamine (50 L, 0.28 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(2S)-2-[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-y]-1,11-dihydroisochrome no[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (32 mg, 40%). MS (ESI) m/z 886 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(N(S(F)(F)[F:29])CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:15][F:29])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2ccnc(Br)c2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2ccnc(Br)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-bromo-pyridin-4-yl)-5-hydroxymethyl-morpholin-3-one (3.25 g, 11.0 mmol), Na2CO3 (3.5 g, 13.06 mmol) in dry THF (15 ml) was added diethylaminosulfur trifluoride (2.25 ml, 17.0 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred for 2 h. Solid Na2CO3 (3.5 g) was again added to the reaction mixture and stirred for 4 h at rt. Solids present in the reaction mixture filtered through Buchner funnel. Filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography using 5% methanol in DCM to obtain title compound as a pale yellow solid. Yield=2.1 g (66%). TLC (50% ethyl acetate in hexane) Rf=0.17; LCMS: RtH7=0.201; [M+1]+=289 and 291; HPLC: RtH9=5.171 min. (50%) and 5.063 (21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][N:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=343.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-chloromethyl-pyridine.
Reaction SMILES: CC(C1C=CC=CC=1)CN.C(Cl)(=O)CC.[CH2:16]([CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH3:28])[CH2:20][NH:19]1)[CH3:17].C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44]>O.C(Cl)Cl>[Cl:41][CH:42]([Cl:46])[C:43]([N:19]1[CH2:20][CH:21]([CH3:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]1[CH2:16][CH3:17])=[O:44]
Reactant: CCC1NCC(C)c2ccccc21
Reactant: O=C(Cl)C(Cl)Cl
Agent: CC(CN)c1ccccc1
Agent: CCC(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccc2cnccc2c1
Solvent: O
Product: CCC1c2ccccc2C(C)CN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method A), β-methyl-phenethylamine and propionyl chloride were converted to 1-ethyl-4-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 8 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1.1 equivalents dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 2 minutes, then water was added. The organic extract was dried with magnesium sulfate and stripped solvent. The residue was recrystallized from cyclohexane to provide 4 g of a white solid product having the elemental analysis reported in Table I.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@H:10]([NH:14][S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]1[O:34][C:33]2[CH:35]=[C:36]([CH2:39]O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:29])[C@H:10]([N:14]([CH2:39][C:36]1[CH:37]=[CH:38][C:32]2[O:31][CH2:30][O:34][C:33]=2[CH:35]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Reactant: OCc1ccc2c(c1)OCO2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Yield: 80.9 %

Procedure:
To a mixture of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyric acid benzyl ester (4.5 g, 10.72 mmol), 3,4-(methylenedioxy)phenylmethanol (2.04 g, 13.41 mmol), and tributylphosphine (3.35 mL, 13.4 mmol) in dry benzene (60 mL) cooled in an ice bath was added 1,1′-(azodicarbonyl)dipiperidine (3.38 g, 13.4 mmol). The reaction mixture was stirred overnight to room temperature and then flash chromatographed on a silica gel column (5-10% ethyl acetate/hexanes) to give 2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (4.8 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1nc(Cl)c(NCCO)nc1N
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCNc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 2, 2-amino-5 chloro-3-cyano-6-[(2-hydroxyethyl)amino]pyrazine (68 mg), was dissolved in pyridine (0.5 ml) and there was then added acetic anhydride (0.5 ml). The reaction mixture was stirred at room temperature for 2 hours, at which point thin layer chromatography showed no starting material remaining. Ice and then water were added to the reaction mixture, after which it was stirred for an additional 15 minutes. The product precipitated, was filtered, washed once with water, and dried (62.7 mg). Elemental Analysis for C9H10N5O2Cl:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:11]=2[C:12]([NH:14][C@@H:15]([CH2:20][CH2:21][S:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:4][CH:3]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:11]=2[C:12]([NH:14][C@@H:15]([CH2:20][CH2:21][S:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1C#Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1C#Cc1ccc(F)cc1

Procedure:
A mixture of compound 55 (2 g), stannous chloride dihydrate(4.4 g) and ethyl acetate (150 ml) was stirred and heated at reflux for 2 hours. It was then cooled and treated dropwise with aequeous ammonia(0.880) to pH 9. The white precipitate formed was filtered and washed with more ethyl acetate (150 ml). The filtrate and washings were combined, dried and evaporated to dryness to give an oil which was purified by flash chromatography on silica using ethyl acetate/iso-hexane as eluant to give methyl (2S)-2-{2-[2-(4-fluorophenyl)ethynyl]-4-aminobenzoylamino}-4-methylsulfanylbutyrate as a yellow solid (compound 56) (1.1 g).
Reaction SMILES: N1CC[C@@H](CN)C1.C([O-])([O-])=O.[Na+].[Na+].C(C(C)=O)C(C)C.ClC1C2C(=CC(C)=CC=2)N=C(C2C(F)=CC=CC=2O)N=1.CC(C)C/C(=[N:46]/[CH2:47][C@@H:48]1[CH2:52][CH2:51][N:50]([C:53]2[C:62]3[C:57](=[CH:58][C:59]([CH3:63])=[CH:60][CH:61]=3)[N:56]=[C:55]([C:64]3[C:69]([F:70])=[CH:68][CH:67]=[CH:66][C:65]=3[OH:71])[N:54]=2)[CH2:49]1)/C>O.C(O)(C)C>[NH2:46][CH2:47][C@@H:48]1[CH2:52][CH2:51][N:50]([C:53]2[C:62]3[C:57](=[CH:58][C:59]([CH3:63])=[CH:60][CH:61]=3)[N:56]=[C:55]([C:64]3[C:69]([F:70])=[CH:68][CH:67]=[CH:66][C:65]=3[OH:71])[N:54]=2)[CH2:49]1
Reactant: C/C(CC(C)C)=N\C[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Agent: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Agent: NC[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of ((S)-pyrrolidin-3-yl)methanamine (0.6 g, 6.0 mmol), Na2CO3 (2.2 g, 21 mmol) and methyl isobutyl ketone (12 mL, 6.0 mmol) under an N2 atmosphere was refluxed overnight using a Dean Stark apparatus. After allowing the reaction to cool to room temperature, 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.73 g, 5.99 mmol) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction was then quenched with water. The aqueous layer was extracted twice with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to obtain a crude material containing 2-(4-((S)-3-((E)-(4-methylpentan-2-ylideneamino)methyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol which was then hydrolyzed by heating at 50° C. in 80 mL of a water/isopropanol mixture (1:1) for 6 hours. The reaction was cooled to room temperature, and the aqueous layer was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 5-20% MeOH and CH2Cl2 afforded 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (400 mg, 19% after 3 steps). LC/MS: m/z 353.1 (M+H)+ at 1.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0797 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol and ethyl acetate. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0819 g, 37.2%): MS ES+ 357.1 (M+H)+, base peak 228.0 (M−C7H14NO)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=7.4 min, 100% purity.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]CO)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:2][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCOCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
179 g of tetrabromomethane is added in portions to the solution of 85 g of 5-benzyloxy-pentan-1-ol and 143 g of triphenylphosphine in 720 ml of methylene chloride that is cooled to −15° C., and after the addition has been completed, it is stirred for 3 hours at 0° C. After the reaction mixture was concentrated by evaporation in a vacuum, the purification is carried out by chromatography on silica gel with a hexane-methylene chloride gradient. 71 g of 5-benzyloxy-1-bromo-pentane is obtained as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2F)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
DIPEA (68 mg, 0.09 mL, 0.53 mmol) was added drop wise to 2,5-difluoro-benzoic acid (33 mg, 0.21 mmol) in DMF (5 mL). EDCI (40 mg, 0.21 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (60 mg, 0.17 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 39 mg (46% yield) of N-{2-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 96.62%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 2H), 7.4 (t, 3H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[O:26][CH2:27][C:28](=O)[CH3:29].C(C1C=C(C(F)(F)F)C=CC=1N1C[C@@H](C)OC2C=C(S(NC3SC=CN=3)(=O)=O)C=CC1=2)#N>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][CH:28]([CH3:29])[CH2:27][O:26][C:3]=3[CH:4]=2)(=[O:10])=[O:9])=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(OCC(C)=O)c2)cc1
Agent: C[C@@H]1CN(c2ccc(C(F)(F)F)cc2C#N)c2ccc(S(=O)(=O)Nc3nccs3)cc2O1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(C)N3)cc1

Procedure:
N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was prepared from 4-amino-N-(4-methoxybenzyl)-3-(2-oxopropoxy)-N-(thiazol-2-yl)benzenesulfonamide in a similar manner to that described for the synthesis of INTERMEDIATE R.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](=O)[CH3:24])=[C:15]1Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].O>CO.CCOC(C)=O>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:23]([CH3:24])=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CS
Reactant: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(c1C)c1ccccc1n2Cc1ccccc1
Reaction time: 8 h

Procedure:
550 μl of methyl 2-mercaptoacetate was added to a slurry of 1.45 g of (82) and 1.6 g of K2CO3 in 15 ml of MeOH, and left with stirring overnight. 30 ml of water was added, and the product isolated as a sticky lump. This lump was dissolved in EtOAc, washed with water, dried and evaporated to give an oil, which slowly solidified. Crystallization from MeOH gave (83). Yield 330 mg. M.p. 132°-4° C.
Reaction SMILES: CO[C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=2[F:43])[CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:33])[CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:26]([CH3:32])=[N:27][CH:28]=[N:29][C:30]=3[CH3:31])=[O:24])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1.[NH3:45]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=2[F:43])[CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:33])[CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:30]([CH3:31])=[N:29][CH:28]=[N:27][C:26]=3[CH3:32])=[O:24])[CH2:15][CH2:14]2)=[CH:10][CH:11]=1)(=[O:44])[NH2:45]
Reactant: N
Reactant: COC(=O)COc1ccc(N(Cc2cc(C#N)ccc2F)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(OCC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
COMPOUND 237 (74 mg, 0.12 mmol) was dissolved in MeOH (15 mL) and NH3(g) was passed through the solution for 10 minutes. The mixture was stirred at room temperature for 1 h then concentrated to give COMPOUND 239 as a yellow foam (72 mg, 100%). 1H NMR (CDCl3) δ 0.92-1.25 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.59 (m, 1H), 1.71-1.82 (m, 3H), 2.17 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.75-2.90 (m, 3H), 3.31-3.46 (m, 2H), 3.83 (m, 1H), 3.97 (s, 2H), 4.41 (s, 2H), 5.60 (br s, 1H), 6.60 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.17 (m, 1H), 7.52 (m, 2H), 8.23 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.42, 21.92, 29.40, 30.42, 31.08, 39.81, 42.94, 43.79, 51.92, 58.25, 59.94, 67.83, 108.52, 115.69, 116.49, 116.80, 117.52, 118.34, 129.01, 129.21, 130.68, 132.73, 132.86, 133.32, 133.39, 142.87, 150.71, 157.58, 161.04, 162.97, 164.43, 166.40, 171.31. ES-MS m/z 588 (M+H). Anal. Calcd. for C32H38N7FO3.1.2CH4O: C, 63.69; H, 6.89; N, 15.66; F, 3.03. Found: C, 63.77; H, 6.68; N, 15.53; F, 2.87.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.C(N(CC)CC)C.CS(O[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([CH3:52])([CH3:51])[CH2:48][CH:49]=[O:50])(=O)=O>C(#N)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][N:19]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([CH3:51])([CH3:52])[CH2:48][CH:49]=[O:50])[CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(CC=O)CCCCCCOS(C)(=O)=O
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCC(C)(C)CC=O)CC3)C2)cs1

Procedure:
(2-Isopropyl-thiazol-4-yl)-(1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-methanone (0.262 g) (prepared from the trifluoroacetate salt as in Example 102, step c) was dissolved in acetonitrile (4 mL) and triethylamine (0.22 mL) was added. This solution was then added to a solution of 7,7-dimethyl-9-oxononyl methanesulfonate (Example 279, step e) (0.291 g) in acetonitrile (4 mL) and the resultant mixture heated at 80° C. overnight. The solvents were removed under vacuum. Purification was by silica gel chromatography eluting with 0-10% Methanol in DCM to afford the subtitled compound as a colourless oil. Yield 0.361 g.
Reaction SMILES: C1(C)C=CC(S([N:10]([CH2:20][CH2:21][N:22](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][CH2:24][N:25](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:36][CH2:37][N:38](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:39][CH2:40][N:41](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:42][CH3:43])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])(=O)=O)=CC=1.[Na+].[Na+].P(=O)(O)([O-])[O-].Cl>CO.O1CCOCC1>[CH2:18]([OH:19])[CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][NH:41][CH2:42][CH3:43]
Reactant: CCN(CCN(CCN(CCCCCCCCCN(CCN(CCN(CCOCCOCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNCCNCCNCCCCCCCCCNCCNCCNCCOCCOCCO

Procedure:
A mixture of 9,12,15,25,28,31-hexa(p-toluenesulfonyl)-9,12,15,25,28,31-hexaaza-3,6-dioxatritriacontanol (1.30 g, 0.92 mmole), Na/Hg (10.85 g), and phosphoric acid disodium salt (1.96 g, 13.8 mmole) in methanol/dioxane (70 ml/40 ml) was heated to gentle reflux for 24 hours. Additional Na/Hg (2.0 g) was then added. The reaction mixture was maintained at reflux for another 24 hours, then cooled. The insoluble material was filtered and washed with CH3OH. The filtrate was concentrated to give an oily residue which was then treated with 2 N HCl (aq) and washed with CH2Cl2 (200 ml×2). The aqueous acidic solution was then made basic with 10% NaOH (aq), extracted with CH2Cl2 (250 ml×3), dried over MgSO4, filtered and concentrated to give a pale yellow oil (0.25 g, 55% crude yield) which was used further without purification. The reaction is shown schematically below: