Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>>[Br:25][C:21]1[CH:20]=[C:19]([C:17]([CH3:16])=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(=O)c1cccc(Br)c1
Product: CCOC(=O)C(C)=C(C)c1cccc(Br)c1

Procedure:
To a suspension of potassium tert-butoxide (183.1 g, 1.63 mol) in toluene (1400 ml) under an atmosphere of nitrogen was slowly added triethyl 2-phosponopropionate (361.1 g, 1.52 mol) with ice cooling at such a rate that the internal temperature was maintained at approximately 20° C. The resultant yellow solution was stirred at room temperature for 3 h after which time it was cooled in an ice bath. To this cooled solution was added a solution of 3-bromoacetophenone (274.2 g, 1.38 mol) in toluene (400 ml) at such a rate that the internal temperature did not rise above 20 ° C. The resultant red-brown solution was then stirred at room temperature for 18 h. After this time, more potassium tert-butoxide (38.7 g, 0.34 mol) was added, and the resultant mixture was stirred at room temperature for an additional 20 h. The reaction was quenched by the cautious addition of water (2000 ml), and the layers were separated. The organic layer was washed with water (4×2000 ml), and was then concentrated in vacuo to give the crude product as a brown oil (344 g) which was distilled under reduced pressure to give the impure title compound (2:3 mixture of geometric isomers) as a colourless liquid (212 g) which was contaminated with small amounts of triethyl 2-phosphonopropionate and 3-bromoacetophenone. In the present synthetic route the impure title compound was taken forward into the next step without any further purification. However, purification, for example using flash chromatography eluting with 5% ethyl acetate in hexane, affords the analytically pure title compound as a clear colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:52][N:53](C(C)C)[CH:54](C)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].CNC>C(Cl)Cl.C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][N:53]([CH3:54])[CH3:52])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of Intermediate 123a (108 mg, 0.159 mmol) and DIPEA (0.083 mL, 0.48 mmol) in DCM (4 mL) was added methanesulfonyl chloride (36.5 mg, 0.318 mmol) and the resulting yellow solution stirred at RT for 20 min. Water (2 mL) and sat. aq. NaHCO3 solution (2 mL) were added, then the aqueous extracted with DCM (4 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a yellow solid. The solid was dissolved in THF (2 mL), then dimethylamine (2 M in THF, 1.6 mL, 3.2 mmol) added, and the mixture stirred at 60° C. in a sealed vial for 18 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (1 mL), applied to an SCX-2 cartridge (5 g), washed with MeOH (20 mL) and eluted with 2 M NH3 in MeOH (20 mL); concentration in vacuo gave a glassy yellow solid (98 mg). MDAP (Method 7) gave a pale yellow solid (63 mg). Additional purification by HPLC (Gemini C18, 15-65% MeCN in water, 0.1% HCO2H, 20 min, ×2) gave the title compound as a white solid (18.6 mg, 17%). LCMS (Method 5): Rt 3.62 min, m/z 706.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.88 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.48-1.56 (2H, m), 1.65-1.71 (2H, m), 1.76-1.96 (4H, m), 2.00-2.14 (2H, m), 2.17 (6H, s), 2.59 (2H, t, J=5.8 Hz), 2.95 (1H, ddd, J=12.2, 8.1, 4.8 Hz), 3.18 (1H, dt, J=12.1, 4.3 Hz), 3.26-3.29 (1H, m), 4.07 (2H, t, J=5.8 Hz), 4.81 (1H, td, J=8.6, 5.6 Hz), 5.53 (1H, t, J=4.3 Hz), 6.31 (1H, s), 6.95 (1H, dd, J=8.4, 2.2 Hz), 7.09 (2H, m), 7.18 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.41 (6H, m), 7.64 (1H, d, J=9.9 Hz), 7.70 (1H, d, J=2.1 Hz), 8.34 (1H, s), 8.50 (0.3H, s).
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:39]([CH:42]([CH2:46][CH2:47][CH3:48])[C:43](Cl)=[O:44])[CH2:40][CH3:41].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:43](=[O:44])[CH:42]([CH2:46][CH2:47][CH3:48])[CH2:39][CH2:40][CH3:41])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CCCC(CCC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCCC(CCC)C(=O)N1CC(NC(=O)Nc2cccc(C(=O)OCC)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 100.4 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), 2-n-propylpentanoyl chloride (174 mg) and pyridine (87 μl) were added, the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, successively washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 625 mg of the titled compound (Yield: 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[C:19]1([CH:25]([NH2:28])[CH2:26][CH3:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1.C(O)(C)C>CCOC(C)=O.CO>[C:17]([N:16]=[C:8]([NH:28][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:26][CH3:27])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Reactant: CCC(N)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CO
Solvent: CC(C)O
Product: CCC(NC(=NC#N)Nc1cccnc1)c1ccccc1
Yield: 48.3 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (13.93 g, 0.05836 mol), 1-phenylpropylamine (8.68 g, 0.0642 mol), N-methylmorpholine (139 mL) and isopropanol (92.9 mL) was refluxed, under nitrogen, for 18 hours. The reaction was complete by TLC with 10% MeOH-1% NH4OH-CHCl3. Concentration of the reaction mixture gave a residue that was mixed with EtOAc and concentrated several times until the product crystallized. The solid was boiled twice with small portions of EtOAc; each time the mixture was cooled and the liquid decanted. The resulting solid was crystallized from MeOH-EtOAc to give 7.87 g (43.8%) of product: mp 155°-156° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.N12CCCN=C1CCCCC2.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH:47]([C:53](=O)[CH2:54][CH2:55][CH3:56])[C:48](OCC)=[O:49])=[CH:42][CH:41]=1)#[N:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>CCN(C1C=CC=CC=1)CC.C(OCC)(=O)C.O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:48](=[O:49])[C:47]([CH2:46][C:43]3[CH:44]=[CH:45][C:40]([C:35]4[C:34]([C:32]#[N:33])=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:41][CH:42]=3)=[C:53]([CH2:54][CH2:55][CH3:56])[N:20]3[N:19]=[CH:18][CH:17]=[C:16]23)=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccn[nH]2)cc1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A solution of N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine (2.8 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.0 g) in diethylaniline (15 mL) was stirred at 180° C. for 8 hr. The mixture was allowed to cool, tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 5 mL) were added, and the mixture was stirred for 1 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.5 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[C:4]([CH:22]2[CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23]2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.O>CO.[Pd]>[NH:24]1[CH2:25][CH:22]([C:4]2[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]3[N:19]=[CH:18][N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][NH:15]4)[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:36])[CH2:23]1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (255 mg, 0.503 mmol) and 5% palladium (125 mg) was combined in methanol (15 mL), to which was added 0.25 M HCl in water (5.0 mL, 1.2 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1. The azetidine intermediate made above was combined with DIPEA (0.26 mL, 1.5 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.19 mL, 2.5 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.32 g, 1.5 mmol). The mixture was stirred at room temperature overnight, then diluted with MeOH and purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:32][C:33]1([N:37]([CH3:39])[CH3:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[C:20]([N:35]2[CH2:36][C:33]([CH3:32])([N:37]([CH3:39])[CH3:38])[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CN(C)C1(C)CNC1
Agent: CS(=O)(=O)O
Product: CN(C)C1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1
Yield: 81.2 %

Procedure:
7-Fluoro-1-methyl-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate. 1.56 g of 7-fluoro-1-methyl-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 274° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH2:26][NH:27]C(OCC4C=CC=CC=4)=O)[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:38])[CH:5]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:38])[CH:5]=1
Reactant: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(C#CCNC(=O)OCc4ccccc4)c3)C2=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(CCCN)c3)C2=O)c1
Yield: 101.2 %

Procedure:
A solution of the Cbz-protected propargylamine 3 (580 mg, 1.1 mmol) and acetic acid (50 μL) in MeOH (10 mL) was stirred over 10% Pd/C (284 mg) under an atmosphere of hydrogen (50 psi) for 18 h. The suspension was passed through a PTFE-filter and the resulting filtrate concentrated under vacuum to give the desired material as a yellow solid (440 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 8.32 (bs, 1H), 8.05 (bs, 2H), 7.83-7.88 (m, 2H), 7.34-7.41 (m, 3H), 7.27 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 4.57 (s, 2H), 3.79 (s, 3H), 3.39 (m, 2H), 2.86 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H), 1.65 (s, 3H). MS (ES+): 396 (M+H), 418 (M+Na).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:16]([O:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][O:15][C:16](=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(c1ccccc1)N(CCO)CCO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCC/C=C\CCCCCCCC)C(=O)c1ccccc1

Procedure:
N,N-bis(2-erucoyloxyethyl)benzamid was prepared by the procedure of example 1 from 19.5 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)benzamide and 71 gms. (0.2 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3N)C(F)(F)F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(F)cc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
9.4 mg of 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 0.04 ml of acetic acid anhydride in 0.5 ml of tetrahydrofuran are stirred for 2 days at room temperature, and mixed with ethyl acetate and sodium bicarbonate solution. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel, 8 mg of 6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](=[O:27])[NH:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:14][CH:13]=1)(C)(C)C.[ClH:29]>>[ClH:29].[ClH:29].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([NH:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[O:27])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Agent: Cl
Product: NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1

Procedure:
(4-{4-[(1H-Imidazol-2-yl-carbamoyl)methoxy]phenyl}butyl)carbamic acid tert-butyl ester 34 (950 mg, 2.45 mmol) was treated with HCl (4 M in dioxane, 24 mL, 96 mmol) at room temperature for 12 h. The reaction mixture was concentrated in vacuo and further co-evaporated with dichloromethane and methanol, and dried under high vacuum. The desired product was obtained as a white solid (779 mg, 98%) and used directly without further purification. 1H NMR (300 MHz, CD3OD) δ 1.59–1.74 (m, 4H), 2.55–2.67 (m, 2H), 2.85–2.98 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.19 (s, 2H). m/z (ESI): 289 [C15H20N4O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: O=C(Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21)N1CCNCC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) piperazine-1-carboxylic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:34]([CH3:38])[CH2:35][CH:36]=[CH2:37].[I-].[K+]>O.CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[CH2:7][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:37][CH2:36][CH2:35][CH:34]=[CH2:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCC(C)Br
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
To a mixture of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV, 91 g, 240 mmol), cesium carbonate (86 g, 264 mmol) and dimethylformamide (240 ml) was added 4-bromopentene (39 g, 264 mmol) and potassium iodide (39 g). After stirring at about 23° C. for about 24 hours, the mixture was heated to about 55° C. After stirring for about 4 hours, the mixture was treated with additional 4-bromopentene (3.94 g, 26.4 mmol) and cesium carbonate (8.61 g, 26.4 mmol) and was stirred at about 65° C. for about 12 hours. The mixture was cooled to about 23° C., diluted with water and was extracted with ethyl acetate. The organic phase was washed 3 times with water, dried over sodium sulfate, filtered and concentrated in vacuo to afford 89 g of [(4-benzyloxy-benzenesulfonyl)-pent-4-enyl-amino]-acetic acid tert-butyl ester (compound of formula XVI) as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[C:33]([Cl:38])=[C:32]([Cl:39])[CH:31]=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[CH:31][C:32]([Cl:39])=[C:33]([Cl:38])[C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 24 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc and yielded 0.16 g of impure product. Then, crystallization from EtOAc/heptane gave 90 mg (37%) of a white solid; mp 208.5-210.0° C.; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (m, 3H), 7.07 (m, 1H), 5.08 (br s, 2H), 3.63 (m, 4H), 3.40 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 3275, 1693, 1671, 1602, 1554, 1449, 1409, 1365, 1319, 1312, 1302, 1254, 1166, 1113, 762 cm−1; MS (EI) m/z 487 (M+), 346, 345, 105, 94, 92, 76, 65, 62, 56, 52; MS (FAB) m/z 488 (M+H+), 488, 487, 434, 433, 432, 431, 388, 57, 42, 41; HRMS (EI) calcd for C25H27Cl2N3O3 487.1429, found 487.1441; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.41; H, 5.70; N, 8.48.