Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:59][O:60][C:61]1[N:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 96 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:18][CH2:19][CH2:20]Cl)[S:9]2(=[O:23])=[O:22])=[CH:4][CH:3]=1.[CH3:24][NH2:25].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:18][CH2:19][CH2:20][NH:25][CH3:24])[S:9]2(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(Cl)cc1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(Cl)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 1-(4-chlorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (27 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (24 mg):
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9]C(=O)OC(C)(C)C.[Br:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[NH2:9][CH2:8][C@H:3]1[C@@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:20]([C:19]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:18]=1[Br:17])=[O:21]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: C[C@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate and 2-bromo-5-methylbenzoic acid. ESI-MS (m/z): 325, 327, [M]+, [M+2]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:62])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:24]([O:56][CH3:57])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:54][CH3:55])[C@@H:34]([CH3:53])[C:35](=[O:52])[NH:36][C@@:37]1([C:46](=[O:51])[NH:47][CH2:48][CH2:49][CH3:50])[CH2:39][C@@H:38]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:62])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:24]([O:56][CH3:57])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:54][CH3:55])[C@@H:34]([CH3:53])[C:35](=[O:52])[NH:36][C@@:37]1([C:46](=[O:51])[NH:47][CH2:48][CH2:49][CH3:50])[CH2:39][C@@H:38]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:108]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CCCNC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C)C[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN2C(=O)C=CC2=O)C(C)C)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.9 mg (9 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S,2R)-2-phenyl-1-(propylcarbamoyl)cyclopropyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3 ml of DMF and then admixed with 10.4 mg (54 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 8.3 mg (54 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 9 μl of N,N-diisopropylethylamine and with 9.5 mg (36 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 4.3 mg (22% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](O)=[O:32]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH2:26][CH2:25][CH2:24][OH:23])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1ccc(C(=O)O)cc1OCCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OC)c(OCCCO)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brown solid. MS 512 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[CH3:15][Mg]Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][C:3]1([OH:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=[C:2]1[CH3:1]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohexenone (245 g, 1.28 mol) was added dropwise to a solution of methyl magnesium chloride (105 g, 1.41 mol) in THF (400 ml) and toluene (1.5 L) at room temperature. The temperature rose to 50° C. The mixture was stirred for additional 45 min, was then cooled to 15° C. and poured on ice. The organic phase was separated and washed with water (0.5 L) and brine (0.5 L), dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 70 cm silverplated column (bp. 83-85° C./0.1 Torr) to yield 208 g (78%) product as a mixture of two diastereomers. 1H-NMR (400 MHz, CDCl3): 5.39 (bs, 1H, 3-H), 5.29-5.24 (m, 1H, 2′-H), 2.26-2.05 (m, 2H, 2′-H), 1.98-1.88 (m, 2H, 4-H), 1.75-1.71 (m, 6H, 2-CH3, 3′-CH3), 1.63 (s, 3H, 4′-H), 1.60 (bs, 1H, O—H), 1.50-1.46 (m, 2H, 5-H), 1.24/1.23 (2s, 3H, 1a,b-CH3), 0.96/0.90 (2s, 3H, 6a,b-CH3) ppm. GC/MS (EI), Isomer a: 208 (M+, 1), 190 (20), 175 (17), 147 (56), 121 (100), 105 (46), 98 (52), 83 (45), 43 (82). Isomer b: 208 (M+, 2), 190 (8), 175 (6), 147 (58), 121 (75), 105 (46), 98 (100), 83 (52), 43 (78). IR (ATR): 3476s, 2967vs, 2922vs, 1450s, 1376s, 1073vs, 921m, 902 m cm−1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:29])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC(=O)O)cc1
Yield: 89 %

Procedure:
A solution of ethyl 3-[(4-{4-[(cyclopropylamino)carbonyl]-5-propyl-1H-1,2,3-triazol-1-yl}phenyl)amino]-3-oxopropanoate obtained in Example 12 and sodium carbonate (0.80 g) in methanol (10 ml)—water (10 ml) was heated under reflux for 2 hr, and the reaction mixture was concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to give the title compound as a colorless powder (0.83 g, 89%).
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.C[C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:24][C@H:23]1[C@@:36]2([CH3:37])[C:19]([C:20](=[CH2:21])[CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:22]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: CCOCOCC
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C[C@H]2C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde-diethylacetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β-methylandrost-4-ene-3,17-dione (0.811 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e. until the starting material had disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alkaline (~1 hour). The organic layer was separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent. Thus the pure 1β-methyl-6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield (0.195 g); I.R. (KBr): 3100 (6=CH2), 1735 (17-oxo), 1680 (3-oxo), 1630, 1660 cm-1 (Δ4 and 6=CH2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[NH2:20])(C)(C)C.[ClH:23]>>[ClH:23].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:20])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(N)=O
Agent: Cl
Product: NCCCCCCCCCCCC(N)=O

Procedure:
[(11-Carbamoylundecyl)carbamic acid tert-butyl ester (7) (0.085 g, 0.27 mmol) was treated with HCl (4 M in dioxane, 2 mL, 8 mmol) at room temperature for 14 hours. The reaction mixture was concentrated in vacuo and further dried under high vacuum. The white solid (0.068 g, 99%) was used directly without further purification: m/z (ESI) 215 [C12H26N2O+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:18])[O:7][C:6]=1[CH3:10])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccoc1C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)oc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.5 %

Procedure:
(The following reaction is carried out under exclusion of light.) Dissolve 2-Methyl-furan-3-carboxylic acid methyl ester (100) (3.60 mL, 28.5 mmol) in chloroform (20 mL) and glacial acetic acid (20 mL) and add NBS (6.90 g, 38.8 mmol) portionwise in between a period of 95 min. Stir the reaction suspension for additional 19 h at rt. Add water to the reaction mixture and extract the aqu. layer with dichloromethane (2 times), wash the combined organic layer with 2M aqu. NaOH, water (3 times) and brine and dry it with Na2SO4 to obtain 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (101) (4.90 g, 78%) as a red brown oil. No further purification. 1H NMR (400 MHz, CDCl3): 2.54 (s, 3H); 3.80 (s, 3H); 6.53 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9](C2C=CC=CC=2)[CH:10]([C:16](=[O:19])[CH2:17][Cl:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CCO>[NH2:28][C:29](=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:4]=1)[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16](=[O:19])[CH2:17][Cl:18])[CH3:36]
Reactant: CCOC(=O)C(C(=O)CCl)C(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C(=C(C)N)C(c1cccc(C(F)(F)F)c1)C(C(=O)CCl)C(=O)OCC
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution of ethyl 2-(m-trifluoromethylphenyl-phenylmethyl)-4-chloro-3-oxobutanoate (8 g) and ethyl 3-aminocrotonate (3.4 g) in EtOH (80 ml) is heated to reflux temperature for 10 minutes, then it is cooled at room temperature and after usual work-up the residue is purified by column-chromatography on silica-gel (300 g, eluent Et2O/isopropylether 50/50) to give 6 g of 2-amino-7-chloro-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-oxo-2-heptene as an oil.
Reaction SMILES: CN1C=C(C2C=CN=CC=2)C(C2C=CC(O)=CC=2)=N1.C([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:38]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[CH:37][N:36]([CH2:45][C:46]([F:49])([F:48])[F:47])[N:35]=2)=[CH:30][CH:29]=1)C1C=CC=CC=1>>[N:42]1[CH:43]=[CH:44][C:39]([C:38]2[C:34]([C:31]3[CH:30]=[CH:29][C:28]([OH:27])=[CH:33][CH:32]=3)=[N:35][N:36]([CH2:45][C:46]([F:48])([F:49])[F:47])[CH:37]=2)=[CH:40][CH:41]=1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Product: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)cc1

Procedure:
Following the procedure for the preparation of 4-(1-Methyl4-pyridin4-yl-1H-pyrazol-3-yl)-phenol but substituting 4-[3-(4-Benzyloxy-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine provided the title compound. MS: (M+H m/z=320.1)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
Using a similar procedure to that described in Example 1, using ethyl acetate:dichloromethane (5:95) as the chromatography solvent, 2-(3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was oxidized to afford the title product; HPLC: tR =6.16, FR=2.0, column A, water:acetonitrile (2:3); MS: m/z=558(M+1). Analysis for C29H30F3N3O5 :
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]([CH2:35][CH3:36])=[N:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[OH:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]([CH2:35][CH3:36])=[N:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)NOCc4ccccc4)cc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)NO)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture of 187 mg (0.387 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (4-benzyloxycarbamoyl-phenyl)-amide and 200 mg 10% Pd/C in 10 mL ethyl acetate and 10 mL methanol was placed on a Parr® hydrogenation appartus and shaken under 30 psi H2 at room temperature for 1 hour. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give a tan solid. Purification on a silica gel column (CH3OH/CH2Cl2 gradient 4%, 10%, 20%, flash) gave 74 mg (49%) of a tan solid: mp 175° C. (dec); HRMS calcd for C22H24N4O3+H: 393.1928. Found: 393.1949.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:6][C:7]([OH:9])=O)([O-:3])=[O:2]>ClCCCl>[N+:1]([CH2:4][CH:5]1[C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:7](=[O:9])[CH2:6]1)([O-:3])=[O:2]
Reactant: O=C(O)CC(C[N+](=O)[O-])c1ccsc1
Solvent: ClCCCl
Product: O=C1CC(C[N+](=O)[O-])c2ccsc21
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 4-nitro-3-(thiophen-3-yl)butanoic acid (3.4 g, 15.9 mmol) in DCE (20 mL) was added PPA (20 g) and the resulting mixture was refluxed overnight. After concentration, the reaction mixture was treated with solid NaOH, followed by addition of water. After stirring for 30 minutes, the mixture was extracted with DCM. The DCM extract was washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (2.3 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)[CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])[CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Yield: 72.8 %

Procedure:
N-(6-Methoxypyrimidin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.060 g, 0.125 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0910 mmol, 73%).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[CH3:19][NH:20][NH2:21]>>[CH3:19][N:20]1[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([NH2:13])=[N:21]1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: CNN
Agent: O=S(=O)(O)O
Product: Cn1nc(N)c(N=Nc2ccccc2)c1N

Procedure:
1-methyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 2-phenylhydrazonomalononitrile (425 mg) and methylhydrazine sulfate (720 mg). The compound was purified by column chromatography and afforded a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:13].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][C:8]1([CH3:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:13])=[C:2]([N:1]=[C:15]=[O:17])[C:10]=2[O:9]1
Reactant: Cc1ccc2c(c1N)OC(C)(C)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1N=C=O)OC(C)(C)C2
Temperature: 80 °C

Procedure:
A 400 mg amount of 7-amino -2,2,6-trimethyl-2,3-dihydrobenzofuran was dissolved in 10 ml of carbon tetrachloride, and 246 mg of triphosgene was added thereto. The reaction solution was heated to 80° C., and 229 mg of triethylamine was slowly added thereto with stirring. Further, the mixture was heated under reflux for 1.5 hr. The reaction mixture was filtered through Celite to remove insolubles. The solvent was removed by evaporation to provide 461 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.C(Cl)Cl.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC(=O)NCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCCOS(C)(=O)=O
Yield: 81.6 %

Procedure:
To a solution of 2.00 g (7.77 mmol) of N-(5-hydroxypentyl)caprylamide and 1.30 ml (9.32 mmol) of triethylamine in50 ml of methylene chloride was added 0.72 ml (9.32 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 1.95 g of the desired compound (74.8%, colorless powder), mp: 67.0°-68.0° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1C=CC=C(C)C=1O.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCCCCCCCCCCC>[Cu]I.O.C(OCC)C>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH2:33]
Reactant: CCCCCCN
Reactant: COc1ccccc1I
Agent: [Cu]I
Agent: Cc1cccc(C)c1O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCCCCCCCC
Product: COc1ccccc1CCCCCCN
Temperature: 80 °C

Procedure:
Copper (I) iodide (10 mg, 0.05 mmol, 5 mol %), anhydrous fine powder potassium phosphate (425 mg, 2.0 mmol) and 2,6-dimethylphenol (24 mg, 0.2 mmol, 20 mol %) were put into a screw-capped test tube with a Teflon septum. The tube was evacuated and back-filled with argon (3 cycles). 2-Iodoanisole (130 μL, 1.0 mmol) and n-hexylamine (158 μL, 1.0 mmol) were added by micro-syringe at room temperature. The reaction mixture was heated at 80° C. for 18 hours. The reaction mixture was then allowed to reach room temperature. Diethyl ether (2 mL), water (2 mL) and dodecane (internal standard, 227 μL) were added. The organic layer was analyzed by GC to give 41% GC yield of N-(2-methoxyphenyl)hexylamine.