Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].II>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][C:19]=1[CH2:18][N:11]1[CH2:10][CH2:9][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1
Reactant: ClCC1=Cc2ccccc2CC1
Reactant: NC(=O)C1(Nc2ccccc2)CCNCC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1

Procedure:
A mixture of 4-anilino isonipecotamide (5.5 g), 3,4-dihydro-2-chloromethylnaphthalene (4.0 g), and powdered sodium carbonate (3.5 g) in toluene (200 ml) containing several crystals of iodine is refluxed for 14 hours with vigorous stirring under nitrogen. The reaction mixture is then cooled, diluted with methylene chloride (100 ml), and filtered. The filtrate is concentrated and the crude product triturated with ethyl acetate (100 ml) to give the title compound.
Reaction SMILES: [Br-].C[N+:3]1[CH:4]=[CH:5][N:6]2[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[C:7]=12.N1C=CN=C1>>[CH3:12][C:10]1[NH:9][C:8](=[O:13])[C:7]2[N:6]([CH:5]=[CH:4][N:3]=2)[CH:11]=1
Reactant: Cc1cn2cc[n+](C)c2c(=O)[nH]1
Agent: [Br-]
Agent: c1c[nH]cn1
Product: Cc1cn2ccnc2c(=O)[nH]1
Temperature: 175 °C
Reaction time: 20 h
Yield: 39.7 %

Procedure:
A mixture of 1,6-dimethyl-8-oxo-7,8-dihydro-imidazo[1,2-a]pyrazin-1-ium bromide salt (4.3 g, 16.4 mmol) and imidazole (20.4 g, 310 mmol) is stirred at 175° C. for 20 h. After this time the reaction mixture is cooled down to 100° C. and poured into ice-water with vigorous stirring. No precipitation is observed therefore the solvent is removed and the imidazole distilled off under vacuum at approx. 130° C. The solid remaining is triturated with DCM to give 6-methyl-7H-imidazo[1,2-a]pyrazin-8-one as a brown solid (970 mg). The mother liq. are purified by column chromatography using a gradient of (DMC/MeOH:99/1 to 95/5) to give a further 667 mg of 6-methyl-7H-imidazo[1,2-a]pyrazin-8-one as a pale yellow solid (1.66 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](Br)[CH:35]=1)[C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C(=O)=O.C([Li])CCC.Cl[Si:50](Cl)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC(C)=O.C1COCC1>[CH:23]1[C:22]2[N:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([N:8]5[C:3]6[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=6[Si:50]([C:57]6[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:34]5=6)[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(N(c2cccc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)c2)c2ccccc2Br)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: c1ccc([Si]2(c3ccccc3)c3ccccc3N(c3cccc(-c4cccc(-n5c6ccccc6c6ccccc65)c4)c3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-(2-bromophenyl)-N-(3-bromophenyl)-3′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-3-amine was added into a 250 mL round bottom flask, and solubilized in dry THF (155 ml). The solution was cooled down to −78° C. using dry ice and Acetone. Butyllithium (7.45 ml, 18.62 mmol) was added dropwise and the reaction mixture was stirred −78° C. for 2 hours. Dichlorodiphenylsilane (2.108 ml, 10.24 mmol) was then added dropwise. The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction was quenched with water, extracted three times with ether, washed with brine and water. The crude material was purified with column chromatography using hexane/DCM (75/25). The product was collected as a white powder with a purity of 99.3% by HPLC. The product was recrystallized twice from DCM and hexane. The target 5-(3′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-3-yl)-10,10-diphenyl-5,10-dihydrodibenzo[b,e][1,4]azasiline (Compound 10) was afforded as a white powder (1.8 g, 29% yield). Compound 10 was then sublimed and 1.2 g was collected.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH3:35])[CH:30]=[N:29][C:28]=2[N:27]([CH3:36])[C:25]1=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]([N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH3:35])[CH:30]=[N:29][C:28]=2[N:27]([CH3:36])[C:25]1=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(O)n1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)n1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of oxalyl chloride (0.11 ml, 1.30 mmol) in dichloromethane (8 ml) at -78° C. was added dimethylsulfoxide (0.20 ml, 2.60 mmol) and over a 5 minute period l-(1 -hydroxydodecyl)-3,7-dimethylxanthine (0.40 g, 1.10 mmol) in dichloromethane (4 ml). The reaction was stirred at -78° C. for 30 minutes and after the addition of triethylamine (0.72 ml, 5.20 mmol), the reaction was allowed to warm to 25° C. over 30 minutes. Water (10 ml) was added, the organic phase separated and the aqueous phase washed with dichloromethane (10 ml). The organic portions were combined and dried with magnesium sulfate, and the solvent evaporated to give a slightly yellow solid. The crude yellow solid was recrystallized from hot hexane to obtain 0.32 g of a white solid, 1-(1-oxododecyl)-3,7-dimethylxanthine (80% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[CH:32][C:31]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl>[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH2:36][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[CH:33]=[CH:32][C:31]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(C=O)cc1NC(=O)OC(C)(C)C
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(NC(=O)OC(C)(C)C)c4)CC3)c2c1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To 10 mL of a methylene chloride solution containing 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 0.19 g of tert-butyl(5-formyl-2-methylphenyl)carbamate and 45 μL of acetic acid were added, and stirred for 30 min. To the reaction mixture, 0.21 g of sodium triacetoxyborohydride was added, and stirred for 10 hours. After allowed to stand overnight, 45 μl of acetic acid was added and stirred for 40 min, then 0.17 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 2 hours and 40 min. 90 μL of acetic acid was further added and stirred for 40 min, then 0.34 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 2 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1], to give 0.28 g of tert-butyl(5-(((1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2-methylphenyl)carbamate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][C:32]1([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH2:34][CH2:33]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1(CO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC2(CO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d, (1-aminomethyl-cyclopropyl)-methanol (30.3 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of MeCN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (23.9 mg, 24.7%) as a white powder.
Reaction SMILES: OC[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C1(CO)C=CC([CH2:17][OH:18])=CC=1.C(=O)C1C=CC(C=O)=CC=1>>[OH:18][CH2:17][C:5]1[CH:4]=[CH:3][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OCc1ccc(CO)cc1
Reactant: O=Cc1ccc(CO)cc1
Agent: O=Cc1ccc(C=O)cc1
Product: O=Cc1ccccc1CO
Reaction time: 0.17 h

Procedure:
167.0 g of sodium carbonate and 1200 g of distilled water were placed in a four-necked flask equipped with a reflux condenser, a lagged dropping funnel, a thermometer and a stirrer, and the atmosphere in the flask was replaced with nitrogen and then adjusted to 100° C. Next, 100 g of α,α,α'-trichloro-p-xylene having a purity of 90% by weight obtained in the same manner as in Preparation Example 1 were added dropwise thereto over 10 minutes. After an aging reaction was carried out for 10 hours, the resultant reaction solution was analyzed by the use of gas chromatography. As a result, it was found that the reaction solution was composed of 85% by weight of p-hydroxymethylbenzaldehyde, 4.8% by weight of p-xylylene glycol, 2.8% by weight of terephthalaldehyde and 7.4% by weight of the others.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+]([O-])=O)=[CH:10][CH:11]=2)[NH:6][C:5](=[O:16])[C:4]1=[O:17])[CH3:2].C[N:19](C)C=O>[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]2[C:7]([NH:6][C:5](=[O:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)C=O
Agent: [Pd]
Product: CCn1c(=O)c(=O)[nH]c2ccc(N)cc21
Yield: 81 %

Procedure:
8.3 g (35 mmol) of 1-ethyl-6-nitro-2,3 (1H,4H)-quinoxalinedione were dissolved in 300 ml of dimethylformamide and, after addition of 2 g of palladium/carbon (10%), were hydrogenated. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 5.9 g (81%) of the product.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc2c(/C=C(\C)C(=O)OCC)cc(OC)c(OCOC)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.45 g, 1.3 mmol) in acetonitrile (10 mL), was added 4-trifluoromethyl-benzoyl chloride (0.30 mL, 2.0 mmol) and N,N-diisopropyl ethylamine (0.58 mL, 3.3 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (420 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (97.2%); mp, 253-255° C.; 1HNMR (DMSO-d6)2.18-2.24 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.94-5.11 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.13 (m, 7H, Ar), 9.16 (t, J=5 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.28, 30.60, 42.31, 56.56, 117.68, 124.28, 125.39, 125.44, 125.57, 125.74, 128.16, 130.99, 131.41, 133.98, 137.96, 140.45, 148.50, 154.89, 161.10, 165.12, 169.54, 172.63. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.5H2O: C, 57.38; H, 4.19; N, 11.64; F, 11.84. Found: C, 57.01; H, 4.05; N, 11.53; F, 11.56.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.F.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: F
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
500 g of anthraquinone and 500 ml of 85 percent strength hydrogen fluoride are initially introduced into a 4 liter Venuleth vessel and stirred for 15 minutes. A mixture of 500 ml of hydrogen fluoride (85 percent strength) and 140 ml of nitric acid (98 percent strength) is added at room temperature over the course of 5 minutes. The bath temperature of the Venuleth vessel is then raised to 50°C and the mixture is stirred at this temperature for 8 hours. The hydrogen fluoride is largely stripped off in vacuo (approx. 50 mm Hg) at the same temperature. The residue is treated with water, filtered off, washed and dried. 610 g of nitro-anthraquinone of the following composition are obtained:
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[N+:13]([CH3:16])([O-:15])=[O:14].C(NCC)C>C1COCC1>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=Cc1ccn2c(I)cnc2c1
Reactant: C[N+](=O)[O-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1ccn2c(I)cnc2c1
Temperature: 55 °C

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carbaldehyde (150 mg, 0.54 mmol) in THF (10 ml) was added nitromethane (88 μl, 1.63 mmol), diethylamine (6 μl, 0.05 mmol) and sieves (300 mg). The reaction mixture was heated at 55° C. for 2 hours before being cooled. The sieves were filtered off and the resulting solution partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford a crude product that was used as is (116 mg). MS: [M+H]+=334.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:23][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and glycine ethyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3 H), 2.43 (t, J=6.1 Hz, 4 H), 3.72 (t, J=6.1 Hz, 4 H), 3.95 (d, J=5.8 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 7.04 (d, J=8.9 Hz, 2 H), 7.77(d, J=8.9 Hz, 2 H), 8.63 (t, J=5.8 Hz, 1 H); MS (ES) m/z: 305.2 (MH+); HRMS Calcd. for C18H22N2O4(M+): 304.1423. Found: 304.1422.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:39])([F:38])[F:37])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:38])([F:39])[F:37])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)C1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Solvent: CO
Product: O=C1OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)CC(O)=C1Cc1nc2ncc(Cl)cn2n1
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.131 g, 0.72 mmol) was added to a solution of example A(228) 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (0.230 g, 0.60 mmol) in MeOH (10 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (53 mg, 0.9 mmoL). After 15 hours the reaction mixture was quenched with concentrated HCl, and concentrated to a residual oil. Purification by flash column chromatography (EtOAc then 0%–5% MeOH in CH2Cl2) gave the product as a white solid (17 mg). 1H NMR (DMSO): δ 1.30–1.80 (brm, 8H), 2.08–2.18 (brm, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.15 (m, 2H), 3.47 (m, 3 H), 6.81 (m, 2H), 7.00(s, 1H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C26H26O4N4ClF3: C, 56.68; H, 4.75; N, 10.17. Found: C, 56.50; H, 4.69; N, 10.20.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:23]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(C(=O)N(Cc1ccccc1)Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
N,N-Dibenzyl-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and dibenzylamine. Yield (58%). HPLC ret. time 3.52 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.36 (d, J=2.1 Hz, 1H), 8.18 (d, J=3.3 Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.54 (m, 1H), 7.43-7.39 (m, 2H), 7.35-7.22 (m, 10H), 4.54 (s, 2H), 4.41 (s, 2H); ESI-MS 369.3 m/z (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.[C:23](O)(=[O:31])[C@@H:24]([C@H:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH:11]1[C:10]2[CH:9]([CH2:8][O:7][C:6]([NH:5][CH2:4][CH2:3][NH:2][C:23](=[O:31])[CH:24]([OH:25])[CH:26]([OH:27])[C:28]([OH:30])=[O:29])=[O:22])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCNC(=O)C(O)C(O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
9H-9-fluorenylmethyl N-(2-aminoethyl)carbamate hydrochloride (Compound 14; 5.00 g, 153.7 mmol) and L-(+)-tartaric acid (Compound 15; 5.89 g, 39.2 mmol) were dissolved by the addition of N,N-dimethylformamide (300 ml) and triethylamine (5.46 ml, 39.2 mmol). Next, 1-hydroxybenzotriazol hydrate (2.52 g, 16.5 mmol) was added, a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.16 g, 16.5 mmol) in N,N-dimethylformamide (200 ml) was added drop by drop, and this was followed by overnight stirring at room temperature. This was concentrated under reduced pressure, the residue obtained was dissolved in ethyl acetate, and the organic phase was washed with a 2N aqueous solution of citric acid. Next, reverse extraction was conducted using aqueous sodium hydrogen carbonate, after which the water phase obtained was washed with ethyl acetate. Under ice cooling, the water phase was rendered acidic with a 2N aqueous solution of citric acid, after which it was extracted with ethyl acetate. The organic phase was washed with saturated brine, after which it was dried with sodium sulfate. After the solid was filtered and concentrated under reduced pressure, crystallization from methanol-diethyl ether was conducted to yield the desired N-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-2,3-dihydroxy-succinamic acid (2.72 g, 42%).