Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Br:26])C(=O)C1>CC(O)=O.O>[Br:26][C:7]1[S:6][C:5]([NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (46.5 g, 172 mmol) is dissolved in AcOH (700 mL). To the resulting suspension, NBS (32.2 g, 181 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:14][C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:47]([O:51][NH2:52])([CH3:50])([CH3:49])[CH3:48].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:47]([O:51][NH:52][C:15](=[O:17])[CH2:14][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc3ccccc3n2)cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acid hydrochloride (1.49 g, 3.35 mmol), 1-hydroxybenzotriazole (0.539 g, 3.52 mmol), 4-methylmorpholine (1.55 mL, 14.9 mmol), and O-t-butylhydroxyl amine hydrochloride (0.464 g, 3.70 mmol) are dissolved in methylene chloride (50.0 mL), and the reaction is cooled to 0° C. To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.35 g, 7.04 mmol), and the reaction is allowed to warm up to room temperature and stir overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with saturated sodium bicarbonate, brine, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (1% methanol/methylene chloride) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C=O)C>[C:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:34]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:35][C:1]=2[CH3:2])=[O:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)NCCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)NCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl)acrylamide was dissolved in 2 ml of DMF. 63.0 mg (0.400 mmol) of benzamidine hydrochloride and 26.0 mg (0.317 mmol) of sodium acetate were added to the obtained solution, and they were stirred at 60° C. overnight. Ethyl acetate was added to the reaction mixture and then the obtained mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: CCI
Reactant: NC(=O)CNC(=S)Nc1c(Cl)cccc1Cl
Product: CCSC1=NCC(=O)N1c1c(Cl)cccc1Cl
Yield: 44.3 %

Procedure:
The title compound was prepared by the procedure described in Example 2 using 27.8 g of 2-[3-(2,6-dichlorophenyl)-thioureido]-acetamide and 31.2 g of ethyl iodide. 12.8 g of the title compound was obtained, m.p. 122°-124° C. Anal. Calcd. for. C11H10Cl2N2O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.62; H, 3.33; N, 9.43. Mass spectrum (+FAB, [M+H]+) m/z 289/291/293. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.72 (s, 1 H), 7.70 (s, 1 H), 7.58 (t, 1 H), 4.50 (s, 2 H), 3.10 (q, 2 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2COC)cc1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Ethyl 2'-hydroxymethyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylate (D54) (0.51 g, 1.5 mmol) was stirred in dry DMF (8 ml) under argon. Sodium hydride (80% dispersion, 0.07 g, 2.3 mmol) was added, and the resulting suspension was stirred for 10 min. Iodomethane (0.19 ml, 3.0 mmol) was added; the mixture was stirred for 30 min, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to a yellow gum. Chromatography on silica gel, eluting with 0-50% ethyl acetate/dichloromethane, gave the title compound (0.34 g, 64%) as a colourless gum, solidifying on standing. A little methyl ester was also present.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cn1
Yield: 81 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 5-bromo-2-methoxypyridine, the title compound was formed in 81% yield as a white solid, mp 218°-222° C. free base: 1H NMR (CDCl3, 250 MHz) 8.28 (d, J=2.5 Hz, 1H), 7.69 (dd, J=2.6, 8.7 Hz, 1H), 7.22 (m, 4H), 6.95 (m, 4H), 6.71 (d, J=8.7 Hz, 1H), 4.28 (s, 1H), 3.93 (s, 3H), 3.48 (s, 2H), 2.91 (m, 2H), 2.78 (dt, J=2.4, 11.7 Hz, 2H), 2.62 (d, J=1.4 Hz, 2H), 2.07 (dt, J=4.4, 12.8 Hz, 2H), 1.75 (m, 2H), 1.59 (s, 1H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (19) hydrochloride salt: Analysis for C27H28N2O2.2HCl.0.5H2O: Calculated: C, 65.59; H, 6.32; N, 5.67 Found: C, 65.48; H, 6.14; N, 5.35
Reaction SMILES: [CH:1](OCC)(OCC)[O:2]CC.[NH2:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([F:31])[CH:20]=2)[O:14][N:13]=1>>[CH:1]([NH:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:21]([F:31])[CH:20]=2)[O:14][N:13]=1)=[O:2]
Reactant: Nc1noc(CCc2ccc(-c3ccccc3)c(F)c2)n1
Reactant: CCOC(OCC)OCC
Product: O=CNc1noc(CCc2ccc(-c3ccccc3)c(F)c2)n1
Yield: 83 %

Procedure:
To triethyl orthoformate (6 ml) was added 3-amino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.10 g, 0.35 mmol). After the mixture was refluxed for 20 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with chloroform after water was added. The extracts were dried with anhydrous potassium carbonate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-formylamino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.091 g, 83% yield): NMR(CDCl3)δ 1.86(d, 3H), 4.40(q, 1H), 7.00-7.65(m, 8H), 9.06(broad, 2H) ppm; IR(nujol) 3275, 1740, 1580 cm-1 ; mass m/e 311 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:41][NH:42][CH3:43].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[N:42]([CH3:43])[CH3:41])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg), dimethylamine hydrochloride (8.5 mg), 4-dimethylamino pyridine (18 mg), EDCl (21 mg) and DIPEA (129 mg) in THF (4 mL) was stirred at room temperature overnight. Then the solvent was removed and the residue was separated by preparative HPLC to give title compound as white solid (7 mg).
Reaction SMILES: F[C:2]1([N+:12]([O-:14])=[O:13])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:4]=[CH:3][C:2]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])C1(F)C=C(C(F)(F)F)C=CC1
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:31][N:10]2[C:11]3[CH:12]=[C:13]([C:24]([O:26]C(C)(C)C)=[O:25])[CH:14]=[CH:15][C:16]=3[C:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]2[C:8]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:7]=2[CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH2:31][N:10]2[C:11]3[CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=[CH:15][C:16]=3[C:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]2[C:8]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
13-Cyclohexyl-3-methoxy-7H-benzo[3,4]azepino[1,2-a]indole-6,10-dicarboxylic acid 10-tert-butyl ester 6-methyl ester 1a (1 g, 1 eq) was dissolved in dry dichloromethane under N2, followed by the addition of trifluoroacetic acid (TFA) (8.88 ml, 60 eq). The solution was stirred at RT for 24 h. The solvent was then removed under reduced pressure. The crude product was triturated with diethyl ether. The crystals were filtered off and dried under vacuum overnight to afford the title product 13-Cyclohexyl-3-methoxy-7H-benzo[3,4]azepino[1,2-a]indole-6,10-dicarboxylic acid 6-methyl ester 13a (89%, 0.86 g); LC-MS: Rt. 3.19 min., m/z 446 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)([O-])=O.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.ClCCl.[Pd]>[N:14]1([CH2:13][CH2:12][N:11]2[CH2:10][CH2:9][S:8][C:7]3[CH:19]=[CH:20][C:4]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:5][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCCC1)CCS2
Agent: [Pd]
Agent: I
Solvent: ClCCl
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)N(CCN1CCCC1)CCS2)c1cccs1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a stirred solution of 6-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (649 mg, 2.212 mmol) in ethanol (5 mL) was added palladium, 10 wt. % on activated carbon (235 mg, 0.221 mmol) as a suspension in ethanol (5 mL). The resulting suspension was stirred under an atmosphere of hydrogen (balloon pressure) for 3 hours (yellow color disappears). The balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (1.262 g, 4.42 mmol) was added to the mixture. The resulting mixture was stirred under argon overnight at room temperature. The mixture was then diluted with dichloromethane and filtered through Celite. The filtrate was then diluted with saturated sodium carbonate and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 25 (438 mg, 53.1%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.38 (brs, 2H), 6.19 (s, 1H), 6.08 (d, J=1H), 3.63-3.58 (m, 2H), 3.40-3.33 (m, 2H), 3.01-2.97 (m, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.49-2.42 (m, 4H), 1.70-1.61 (m, 4H); ESI-MS (m/z, %): 373 (MH+, 62), 276 (100); HRMS calculated for C19H25N4S2 (MH+), calculated: 373.1515, observed: 373.1512; HPLC purity: 97% by area.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=1)[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:43]3[CH:44]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 31 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.43 g, 0.84 mmol) and (5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (0.30 g, 0.84 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (0.32 g, 1.7 mmol), and the vial was sealed and heated to 85° C. overnight. The reaction was then cooled to rt and excess NH3 in MeOH (10% in DCM) was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 40 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (0.23 g, 0.26 mmol, 30% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.29 (d, J=6.2 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.03 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.56 (s, 1H), 7.42-7.31 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 2H), 6.90 (t, J=6.6 Hz, 1H), 6.78 (s, 1H), 6.57 (d, J=5.3 Hz, 1H), 4.23 (q, J=7.3 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.31-3.26 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.63-2.46 (m, 6H), 1.40 (t, J=6.8 Hz, 3H), 1.22 (t, J=6.9 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). MS (ESI) m/z=824 [M+H]+.
Reaction SMILES: CN1[C:7]([CH3:8])=[CH:6][C:5](=O)[CH:4]=[C:3]1[CH3:10].[C:11](Cl)([Cl:13])=[O:12]>>[CH2:3]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([Cl:13])=[O:12])[CH3:10]
Reactant: Cc1cc(=O)cc(C)n1C
Reactant: O=C(Cl)Cl
Product: CCCCC(CC)C(=O)Cl
Yield: 89 %

Procedure:
This time, 10 mmols of N-methyl-2,6-dimethyl-4-pyridone were used and 117 g of phosgene were introduced in the course of 2 and a half hours. A yield of 89% of 2-ethylhexanoyl chloride was obtained, after distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].[C:33](=O)([O:41]C1C=CC([N+]([O-])=O)=CC=1)[O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)CC)(C)C>>[CH3:38][Si:37]([CH3:40])([CH3:39])[CH2:36][CH2:35][O:34][C:33]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][CH2:22][O:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:30]([O-:32])=[O:31])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:41]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.5 %

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-6-nitro-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one (200 mg in 5 mL dicloroethane) was added 136 mg of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate followed by 0.092 mL diisopropylethylamine and the mixture heated to reflux. After 20 hours, the reaction was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) to give the title compound (183 mg.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19](N)=[CH:18][CH:17]=1.CC1C=CC(C)=C(C)C=1C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccc(C)c(C)c1C
Product: COc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Yield: 33.4 %

Procedure:
A mixture of 10 g of 4-chloro-1,2-dinitrobenzene, 6.5 g of 4-methoxyaniline and 16 g of 1,2,3,4-tetramethylbenzene is refluxed for 15 hours. After cooling, water is added, the mixture is extracted with AcOEt, washed with a 1N solution of HCl , with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is taken up with iso ether, a gummy insoluble material is separated off and the filtrate is chromatographed on alumina using iso ether as the eluent to give 4.6 g of the expected product after crystallization from isopropanol. M.p.=98° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Cl:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O.O>[ClH:15].[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1nc2ccccc2s1
Temperature: 95 °C

Procedure:
11.8 g phenylalanine (71.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95° C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.CO.[H][H]>[Pd].C(O)(=O)C>[OH:24][C@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: [H][H]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 14 h
Yield: 66.5 %

Procedure:
A mixture of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (33.7 g, 84.7 mmol), methanol (60 ml), acetic acid (60 ml), and 10% palladium on carbon (6 g) was treated with hydrogen gas (40 psi) on a Parr shaker. After 14 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol/ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-3-methylxanthine (15 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9](CCCCBr)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:17].[I-].[K+]>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:10][CH2:11][CH2:6][CH2:7][NH2:2])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:17]
Reactant: CN1C(=O)COc2ccc(CCCCBr)cc21
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1C(=O)COc2cc(CCCCN)ccc21
Reaction time: 72 h

Procedure:
In a 250 cm3 ground-necked flask, 8.1 g (0.03 mol) of 4-methyl-6-(4-bromobutyl)2,3-dihydro-3-oxo-1,4-benzoxazine and 0.9 g of potassium iodide are dissolved in 120 cm3 of methanol and 30 cm3 of chloroform. A stream of gaseous ammonia is bubbled into the solution to the point of saturation, equivalent to approximately 2.6 g of ammonia, and a reflux condenser is then fitted. The temperature is stabilized at 50° C. with an oil bath and the mixture is left stirring magnetically for 72 hours. After cooling, the reaction mixture is evaporated on a water bath under vacuum. The residue is ground with distilled water acidified with 5% HCl solution, and then drained. The filtrate is recovered, washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with chloroform, leaving the 2 phases agitating for 1/2 hour, and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is evaporated on a water bath under vacuum, the residue is then taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The product is dried and then recrystallized in absolute ethanol.