Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([NH:40][CH2:41][CH2:42][CH2:43][NH2:44])([CH3:39])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][CH2:41][NH:40][C:37]([CH3:39])([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CC(C)(C)NCCCN
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNC(C)(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 79.6 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1,1-dimethylethyl)-1,3-propanediamine (0.042 mL, 0.26 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (27 mg, 80%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 12H), 1.12 (m, 2H), 1.56 (m, 2H), 1.70 (m, 2H), 2.31 (s, 3H), 2.48 (m, 2H), 3.12 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@H:40]2[CH3:39])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: C[C@@H]1COCCN1
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (see Preparation 420) and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=610.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](O)=[O:41].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)CN(C)C)CC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of Example 146C (0.048 g, 0.088 mmol), 2-(dimethylamino)acetic acid (0.011 g, 0.102 mmol), N-methylmorpholine (0.019 mL, 0.177 mmol), and 1-hydroxybenzotriazole hydrate (0.007 g, 0.044 mmol) in N,N-dimethylformamide (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.025 g, 0.133 mmol), and the reaction was stirred at ambient temperature for 6 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The material was used directly in the next step without further purification. MS APCI(+) m/z 627.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]3[CH:28]4[CH2:33][CH:30]([CH2:31][CH:32]=3)[C:29]4([CH3:35])[CH3:34])=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]3[CH:28]4[CH2:33][CH:30]([CH2:31][CH:32]=3)[C:29]4([CH3:35])[CH3:34])=[CH:22][CH:23]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCCC3=CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCC3=CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Reaction time: 36 h
Yield: 78.6 %

Procedure:
A mixture of the product of Step C (0.07 g, 0.14 mmol), and 10% Pd/C (0.05 g) in EtOH (5 ml) was stirred for 36 h under H2. The catalyst was removed by filtration through Celite pad and filtrate evaporated to dryness, to give the title product (0.055 g; 78%), as colourless paste. 1H-NMR (CDCl3) 1.02 (s, 3H); 1.18 (s, 3H); 1.39 (s, 3H); 1.41 (s, 3H); 1.46 (s, 9H); 1.84-2.35 (m, 13H); 2.45-2.6 (m, 2H); 3.65 (d, 2H, J=11.8 Hz); 3.84-3.92 (m, 4H); 4.94 (broad s, 1H); 6.77 (d, 2H, J=8.6 Hz); 7.05 (d, 2H, J=8.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 270 mg (1.43 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 513 mg (2.67 mmol) of EDC and 241 mg (1.78 mmol) of HOBT are dissolved in 7.8 ml of DMF. After stirring for 15 min, 0.75 ml (5.4 mmol) of TEA and 510 mg (0.89 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 25f in 3.7 ml of DMF are added. After 20 hours, the mixture is worked up analogously to Example 25g to yield the title compound: HPLC20-100 : tRet =18.5; FAB MS (M+H)+ =743.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([Cl:29])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Reaction time: 2 h

Procedure:
To a stirred slurry of 2-(2,4-di-t-butyl phenoxy) propionic acid (27.8 g, 0.100 mol) in CH2Cl2 (280 mL) with 2 mL of DMF, oxalyl chloride (17.0 g, 0.134 mol) was added dropwise. The solution resulted after several minutes was stirred for 2 hr. TLC indicates no starting material. The solution was filtered through a glass wool plug to remove some debris and the filtrate was concentrated in vacuo, residue was washed with CH2Cl2 (50 mL) and was concentrated once more to give a gelatinous mixture, which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]3[NH:35][C:34]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:33][CH:32]=3)[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].[O:58]1[CH2:62][CH2:61][CH2:60][C@H:59]1[C:63](O)=[O:64].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:45][CH:43]([CH3:44])[C@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:41](=[O:51])[N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:34]1[NH:35][C:31]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:18]4[CH:17]=[CH:16][C:15]([C:12]5[NH:11][C:10]([C@@H:6]6[CH2:7][CH2:8][CH2:9][N:5]6[C:3](=[O:4])[C@@H:2]([C:52]6[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=6)[NH:1][C:63]([C@H:59]6[CH2:60][CH2:61][CH2:62][O:58]6)=[O:64])=[N:14][CH:13]=5)=[CH:20][CH:19]=4)[CH:22]=3)[CH:27]=2)=[CH:32][N:33]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)[C@H]6CCCO6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a 0° C. solution of methyl (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-amino-2-phenylacetyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (70 mg, 0.08 mmol) in DMF (1 mL) was added (S)-tetrahydrofuran-2-carboxylic acid (10 mg, 0.09 mmol), PyBOP (52 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol), and N-methylmorpholine (40 mg, 0.4 mmol) successively. The solution was warmed to rt and allowed to stir for 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, sat. NaHCO3, and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (9.5 mg). LCMS-ESI+: calc'd for C50H54N8O6: 863.01 (M+); Found: 863.31 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CNCCN1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCNCC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperazine to give 262. MS: (ESI+)=382.1
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][NH:3]1.[CH3:25][N:26](C)C=O.[Cl-].[K+].N#CBr>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]#[N:26]
Reactant: CN(C)C=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Agent: N#CBr
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C#N)OCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of 3.25 g (10 mmol) of (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 20 ml of dimethylformamide, 2.76 g (20 mmol) of potassium chloride and 1.80 g (17 mmol) of cyanogen bromide was stirred at room temperature for 20 h. After pouring into water, the precipitated crystals were filtered off, and washed with water to yield 3.34 g (95%) of the title compound, Mp.: 172-176° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:15][OH:16])([CH2:13][CH3:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.CCOCC>[CH2:1]([O:8][CH2:9][C:10]([CH2:13][CH3:14])([CH:15]=[O:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CO)(CO)COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(C=O)(C=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Benzyloxymethyl-2-hydroxymethyl-butan-1ol (9.7 g.) was added to a stirred suspension of pyridinium chlorochromate (9.7 g.) and anhydrous sodium acetate (2.0 g.) in dry dichloromethane (200 ml.) at 0°, under a current of nitrogen. The mixture was stirred at room temperature for six hours. The mixture was diluted with dry ether (200 ml.) and the organic solution was decanted off. The oily residue was treated with ether and the combined extracts were evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:2 ether:hexane. 2-Benzyloxymethyl-2-ethyl-propandial was obtained as a pale brown oil (3.3 g.) and was used immediately.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24][N:29]2[C@@H:28]([CH3:27])[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)cc(C(F)(F)F)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1
Product: COc1ccc(NC(=O)c2cccc(OC)c2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 57 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (0.81 mmol) and 2-amino-N-(4-methoxyphenyl)-3-methoxybenzamide (0.73 mmol) yielded 0.18 g (57%) of the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCC=CCO)c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl palmitate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 26 gms (0.1 mole) of palmitoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:9].[C:32](Cl)(=[O:34])[CH3:33].C[N+]([O-])=O>C(Cl)Cl>[C:32]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:20]([F:31])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:6]=3[F:5])[CH:12]=2)[NH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(C)=O)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 64 %

Procedure:
A slurry of aluminum trichloride (0.270 g, 2.03 mmol) was added to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in DCM (0.7 mL) at 0° C., and the reaction mixture was allowed to stir at 0° C. for 40 minutes. Acetyl chloride (0.0271 mL, 0.380 mmol) was added, and the mixture was allowed warm to room temperature overnight. CH3NO2 (200 μL) was added, and the reaction mixture was sonicated for 2 minutes, and allowed to stir at room temperature overnight. The reaction mixture was quenched with ice and then partitioned between aqueous sodium bicarbonate and EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (5% MeOH/EtOAc) to yield N-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (71 mg, 64%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.98-8.99 (m, 1H), 8.63-8.64 (m, 1H), 8.04 (s, 1H), 7.49-7.54 (m, 1H), 7.15-7.18 (m, 1H), 3.10-3.30 (m, 2H), 2.55 (s, 3H), 1.93-2.00 (m, 2H), 1.09-1.13 (m, 3H); m/z (APCI-pos) M+1=437.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:17]=[N:18][NH:19][N:20]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:20]=[N:19][N:18]([CH3:22])[N:17]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)c1nn[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc([C@@H](NC(=O)OCc2ccccc2)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A suspension of benzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (0.41 g, 1.4 mmol), potassium carbonate (1.0 g, 7.0 mmol) and methyl iodide (0.35 mL, 5.6 mmol) in acetone (7 mL) was stirred at 0° C. for 10 min and warmed to rt. After 5 h, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (8/1-4/1-1/1) to afford 0.29 g (68%) of the title compound.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1>CO>[C:8]1([S:7]([F:19])([F:6])([F:16])([F:17])[F:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CO
Product: FS(F)(F)(F)(F)c1ccccc1

Procedure:
Diazonium salt 1 reacted slowly in MeOH at room temperature to give Ph-SF5 as a major product along with p-SF5—C6H4OH and p-SF5—C6H4OMe as minor products. The rate of dediazoniation was found to increase in warm MeOH; the reaction was nearly complete after 90 min. The observed product distribution, seen in FIG. 9, is consistent with homolytic dediazoniation as the predominant mechanistic pathway (Zollinger, in: Diazo Chemistry I, VCH Verlagsgesellschaft, Weinheim, Germany, 1994, chapter 8).
Reaction SMILES: I[CH2:2][C:3]1([CH3:13])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1.CCN(CC)CC>CO.[Pd]>[CH3:2][C:3]1([CH3:13])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1
Reactant: CC1(CI)CN2CCNC[C@H]2CO1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)CN2CCNC[C@H]2CO1
Yield: 65.6 %

Procedure:
(9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (53 mg, 0.179 mmol) was dissolved in MeOH (5 ml) and Et3N (0.037 mL, 0.268 mmol) was added. The flask was purged with Ar, and Pd/C (19.05 mg, 0.018 mmol) was added. A balloon with H2 was attached and the flask was evacuated and filled with H2 3×. The reaction was stirred over the weekend. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo to give (S)-3,3-dimethyloctahydropyrazino[2,1-c][1,4]oxazine (20 mg) as a yellow solid. The crude material was taken onto the next step.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH:12]=[N:13][CH:14]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cncc(Br)c1)C1CC1
Reaction time: 15 h

Procedure:
Cyclopropanesulfonyl chloride was added dropwise to a solution of 5-Bromo-pyridin-3-ylamine (346 mg, 2 mmol), 4-dimethylaminopyridine (25 mg, 0.205 mmol) and triethylamine (0.558 mL, 4 mmol) in dichloromethane (4 mL) at room temperature under nitrogen. The reaction was stirred at this temperature for 15 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the resulting solution was washed with saturated NaHCO3 solution (25 mL). The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (0-10% CH3OH in CH2Cl2 v/v) and 248 mg of the desired product as a white solid was obtained. ESI-MS m/z: 278.9 [M+1]+, Retention time 1.02 min; 1HNMR (MeOD, 400.342 MHz) δ 1.00-1.10 (m, 4H), 2.63-2.69 (m, 1H), 3.31 (s, 1H), 7.94 (t, J=2 Hz, 1H), 8.39 (s, 1H), 8.40 (d, J=2 Hz, 1H).