Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN(C)CCOc1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OCCN(C)C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 57.2 %

Procedure:
A mixture of 5-bromo-3-(5-(2-(dimethylamino)ethoxy)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 268c (205 mg, 0.56 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (270 mg, 0.56 mmol), PdCl2(dppf) (51 mg, 0.07 mmol), K3PO4 (100 mg), and NaOAc (40 mg) in MeCN (6 mL) and water (2 mL) was heated at 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give 297a (206 mg, 50%). MS: [M+H]+ 643.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)CC.N>>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1
Agent: N
Solvent: CCC(=O)O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a mixture of 100 grams (1.0 mole) of hydantoin, 106 grams (1.0 mole) of benzaldehyde, and 370 grams (5.0 moles) of propionic acid, there were added 17 grams (1.0 mole) of ammonia. The mixture was subsequently held for 3 hours at reflux temperature. After the cooling off, there were obtained 178 grams of 5-benzylidene hydantoin, corresponding to 95% of theory based on hydantoin.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]([S:17][CH2:18][C:19]2[N:20]=[C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=3[C:35]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])=[O:26])[S:22][CH:23]=2)=[N:11][N:10]=1)(C)(C)C.Cl>>[NH2:7][CH2:8][C:9]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]([S:17][CH2:18][C:19]2[N:20]=[C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=3[C:35]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:36])=[O:26])[S:22][CH:23]=2)=[N:11][N:10]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CSc3nnc(CNC(=O)OC(C)(C)C)n3C3CC3)cs2)c(C(=O)C2CCCC2)c1
Agent: Cl
Product: Cc1ccc(NC(=O)Nc2nc(CSc3nnc(CN)n3C3CC3)cs2)c(C(=O)C2CCCC2)c1
Yield: 99.7 %

Procedure:
1-[4-(5-Aminomethyl-4-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (51 mg, 99%) was prepared from (5-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl sulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-ylmethyl)-carbamic acid tert-butyl ester (61 mg, 0.10 mmol) and hydrochloric acid (4 mL, 4.0 M. in dioxane) following the general deprotection procedure.
Reaction SMILES: I[Si](C)(C)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:25][CH2:24][CH2:23][C@@H:22]3[N:17]2[C:18](=[O:26])[CH2:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=1)([O:8][CH3:9])=[O:7].CN(C)CCN(C)C.[I:35]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:25][CH2:24][CH2:23][C@@H:22]3[N:17]2[C:18](=[O:26])[CH:19]([I:35])[CH2:20][CH2:21]3)=[CH:12][CH:11]=1)([O:8][CH3:9])=[O:7]
Reactant: II
Reactant: COC(=O)c1ccc([C@H]2CCC[C@H]3CCCC(=O)N32)cc1
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Iodotrimethylsilane (0.1 mL) was added to a solution of (6R*,9aS*)-6-(4-carbomethoxyphenyl)octahydroquinolizin-4-one (125 mg) and N,N,N′,N′-tetramethylethylenediamine (0.23 mL) in methylene chloride (10 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. Iodine (166 mg) was added to the reaction solution, which was then stirred at 0° C. for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 180 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([N+:27]([O-])=O)=[CH:19][N:18]=2)[CH2:12][CH2:11]1)=[O:9]>[Pd].CO>[NH2:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:9])[CH2:11][CH2:12]2)=[N:18][CH:19]=1
Reactant: O=C(c1ccccc1F)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(OC2CCN(C(=O)c3ccccc3F)CC2)c2ccccc12

Procedure:
Stir a suspension of (2-fluoro-phenyl)-[4-(4-nitro-isoquinoline-1-yloxy)-piperidin-1-yl]-methanone (5.85 g, 14.8 mmol) and palladium on carbon (10%, 2.9 g) in methanol (250 mL) under hydrogen overnight. Remove the catalyst by filtration. Concentrate the filtrate to yield a pale yellow solid (4.7 g, 87% yield, ES+ (m/z) 366.3 [M+H]).
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[O:18][CH3:19])(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CCSC)N.CCN=C=NCCCN(C)C.[CH3:42][O:43][C:44](=[O:67])[C@H:45]([CH2:63][CH2:64][S:65][CH3:66])[N:46](C(=O)C1C=CC(N)=CC=1)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>>[CH3:42][O:43][C:44](=[O:67])[C@H:45]([CH2:63][CH2:64][S:65][CH3:66])[N:46]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH2:8])=[C:10]([O:18][CH3:19])[CH:11]=1)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(OC)c1
Yield: 57.2 %

Procedure:
N-BOC-4-amino-3-methoxybenzoic acid (0.35 g, 1.31 mmol) was reacted with methionine methyl ester hydrochloride (0.9 g, 1.43 mmol) using EDCI as in N-BOC-4-aminobenzoyl methionine methyl ester. After recrystallization from ethyl acetate and hexanes, 0.36 g (57.2 %) of pure product was obtained. mp 163°-165° C.; 1H NMR (CDCl3) 1.53 (9 H, s), 2.09-2.18 (4 H, m), 2.23-2.35 (1 H, m), 2.60 (2 H, t, J=6.9 Hz), 3.80 (3 H, s), 3.93 (3 H, s), 4.92 (1 H, br s), 6.93 (1 H, d, J=7.6 Hz), 7.25 (1 H, m), 7.31 (1 H, d, J=10.2 Hz), 7.44(1 H, s), 8.15(1 H, d, J=8.5 Hz); 13C NMR (CDCl3) 15.47, 28.23, 30.09, 31.48, 52.06, 52.54, 55.81, 80.82, 98.06, 109.38, 116.66, 119.31, 131.52, 147.23, 152.31, 166.57, 172.58; m/ z (FAB) 413 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@:14]1([CH3:19])[OH:18].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O.O.CCOC(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@:14]2([OH:18])[CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@]1(O)CCC[C@@H]1N
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(N[C@H]2CCC[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 130 °C
Yield: 24 %

Procedure:
In a sealed pressure vessel, a mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (1.2 g, 7.08 mmol), (1R,2S)-2-amino-1-methyl-cyclopentanol (1.63 g, 14.2 mmol) and lithium carbonate (1.10 g, 14.9 mmol) in DMSO (14.4 mL) and water (1.4 mL) is heated at 130° C. overnight. After allowing the reaction to cool to room temperature, the mixture is diluted with EtOAc and washed twice with 1 N hydrochloric acid. The organic phase is concentrated under reduced pressure and purified using radial chromatography eluting with EtOAc/hexanes (20 to 50% EtOAc/hexanes gradient). The resulting residue is repurified using radial chromatography with 1% methanol/dichloromethane. The isolated product is recrystallized with ether/hexanes, collected by filtration, and dried under reduced pressure to yield the title compound as a white solid (450 mg, 24%). A second crop (84 mg) is also isolated. LC-ES/MS m/z (35Cl/37Cl) 265/267 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 3H), 1.71-1.73 (m, 5H), 2.12-2.13 (m, 1H), 2.14 (s, 3H), 3.46-3.50 (m, 1H), 4.93 (s, 1H), 5.26-5.30 (m, 1H), 6.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H). Chiral HPLC showed the material had an enantiomeric excess of 67%. The enantiomeric excess is determined by SFC on a CHIRALPAK® AS-H (4.6×150 mm, 5 μm) column using 20% ethanol/carbon dioxide. Flow rate: 5 mL/min. Detection: 225 nm. Isomer 1 (title compound): TR=1.39 min; Isomer 2: TR=1.99 min. The absolute stereochemistry of Isomer 1 (1S,2R) is known by correlation of retentions times with Isomer 1 and Isomer 2 as described in Example 3.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([N:14]2[CH2:22][CH2:21][C:17]3([CH2:20][NH:19][CH2:18]3)[CH2:16][CH2:15]2)=[O:13])=[N:9][CH:10]=1.[CH3:23][C:24]1([CH3:41])[C:28]([CH3:30])([CH3:29])[O:27][B:26]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=O)[CH2:35][CH2:34]3)[O:25]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][C:17]3([CH2:20][N:19]([CH:36]4[C:37]5[C:33](=[CH:32][C:31]([B:26]6[O:27][C:28]([CH3:30])([CH3:29])[C:24]([CH3:41])([CH3:23])[O:25]6)=[CH:39][CH:38]=5)[CH2:34][CH2:35]4)[CH2:18]3)[CH2:21][CH2:22]2)=[O:13])=[N:9][CH:10]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CNC3)nc1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(B5OC(C)(C)C(C)(C)O5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[(5-Methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]nonane dihydrochloride (2-1b, 1.8 g, 5.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 2.0 g, 7.75 mmol) were dissolved in anhydrous dichloroethane (50 mL). Triethylamine (2.88 mL, 20.6 mmol) was added to the solution followed by titanium(IV) isopropoxide (3.06 mL, 2.09 g) and the reaction mixture was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (4.38 g, 20.7 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction was quenched by the addition of 20 mL saturated sodium bicarbonate. The aqueous solution was washed with 100 mL of dichloromethane and the organic solution was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent under vacuum afforded the crude product (4.0 g) as a brown foam. The crude product was purified by silica chromatography on an Analogix system (Analogix Inc., Burlington, Wis.), eluting with 1-10% MeOH in CH2Cl2 to give the title compound (2-1c) as a brown paste (1.1 g, 41%). MS (ES+) 518.6 (M+H)+. 1H NMR (CDCl3) δ1.27 (s, 12H), 1.50-1.65 (m, 4H), 1.76-1.85 (m, 1H), 1.99-2.10 (m, 1H), 2.64-2.76 (m, 1H), 2.90-2.98 (m, 1H), 3.00-3.13 (m, 4H), 3.42 (d, 4H), 3.77 (s, 3H), 3.80 (s, 2H), 3.85 (s, 1H), 7.08-7.12 (m, 1H), 7.18-7.22 (m, 2H), 7.54-7.58 (m, 1H), 7.63 (s, 1H), 8.14-8.16 (m, 1H).
Reaction SMILES: C(OC([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][O:14][C:13]=2[C:12]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][N:32]([CH:52]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60]>C(Cl)Cl>[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60].[CH:52]1([N:32]([CH2:31][CH2:30][NH:22][CH2:21][CH2:20][C:12]2[C:13]3[O:14][CH2:15][C:16](=[O:19])[NH:17][C:18]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCCC3)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl(2-(N-cycloheptyl-3-(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanamido)ethyl)carbamate (280 mg), DCM (5 mL) and TFA (2.50 mL) was stirred at 25° C. for 30 min. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (84 mg). MS [M+H]+=605.3 (calc=605.3451) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 4.12 (s, 3H), 3.88-3.78 (m, 1H), 3.72 (t, J=6.7 Hz, 2H), 3.71 (t, J=6.0 Hz, 2H), 3.48-3.42 (m, 2H), 3.12 (t, J=7.3 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.86 (t, J=6.9 Hz, 2H), 2.62 (t, J=5.9 Hz, 2H), 1.78-1.38 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[C:3]=1[CH3:13].[CH3:14]OC(OC)N(C)C.N1CCCC1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.[Fe].CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1ccc(Br)c2cc[nH]c12
Temperature: 90 °C
Yield: 44 %

Procedure:
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitro-benzene (31 g, 0.126 mol) in DMF (150 mL) was added dimethylformamide dimethylacetal (27 mL) and pyrrolidine (10.5 mL, 0.127 mol). The mixture was heated at 90° C. for 18 h and cooled to r.t. The mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was dissolved into HOAc (50 mL) and added dropwise to a solution of Fe (20.5 g, 0.37 mol) in boiling HOAc (150 mL). The mixture was refluxed for 1 h and cooled to r.t., water added and the mixture was neutralised with Na2CO3, and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EtOAc=5/1) to give the title compound (13 g, 44%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1I
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: Clc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 24 h
Yield: 31.2 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-2-chloro-benzene (7.34 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 2.59 g (31%) of the title compound: mass spectrum (ion spray): m/z=405.4 (M+1); Analysis for C26H29ClN2: calcd: C, 77.11; H, 7.22; N, 6.92; found: C, 77.12; H, 7.13; N, 7.07.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20].CN1C2N=CN(C)C=2C(=O)N(CCCCC(=O)C)C1=O.C[Mg]Cl.[Br-].C(N1C2C(=O)NC(=O)N(C)C=2N=C1)C1C=CC=CC=1>>[OH:22][C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:4]1[C:5](=[O:12])[C:6]2[N:7]([CH3:11])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: CC(C)(O)CCCCCl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: CC(=O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: C[Mg]Cl
Agent: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: Cn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
Alternatively, it was possible, inter alia, to prepare the compound from 3,7-dimethylxanthine and 1-chloro-5-hydroxy-5-methylhexane analogously to Example 2 or 4, from 3,7-dimethyl-1-(5-oxohexyl)-xanthine and methylmagnesium chloride or bromide analogously to Example 9, and from the compound of Example 6 and a methylating agent analogously to Example 3.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@H:4]([CH2:42][CH2:43][S:44][CH3:45])[NH:5][C:6](=[O:41])[CH2:7][N:8]([CH2:20][C@@H:21]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CO>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:46])=[O:2])[CH2:42][CH2:43][S:44][CH3:45])=[O:41])=[O:40])=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
The methyl ester from Step F (87 mg, 130 μmol) was dissolved in MeOH (1 ml) and 1.00N NaOH (300 μl, 300 μmol) was added. The mixture was stirred at 45° C. under argon for 45 minutes, then the solution was partitioned between EtOAc (100 ml) and 5% citric acid (50 ml). The organic layer was washed with H2O (2×50 ml), dried (MgSO4), filtered and evaporated to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=[O:17])(=O)=O.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:11]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=[O:17])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCCc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=Cc1ccc(OCCc2ccccc2)c(COc2ccccc2)c1
Reaction time: 48 h

Procedure:
Cesium carbonate (226 mg, 0.69 mmol, 1.5 eq) was added to a stirred solution of 3-[[(methylsulfonyl)oxy]methyl]-4-(2-phenylethoxy)benzaldehyde (155 mg, 0.46 mmol, 1 eq) and phenol (175 mg, 1.86 mmol, 4 eq). The reaction mixture was stirred for 48 h, then partitioned between diethyl ether (50 mL) and water (50 mL). The two layers were separated and the organic layer washed with water (2×100 mL), 1M sodium hydroxide (100 mL), brine (100 mL) and then dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel. Elution with dichloromethane gave a gummy solid, which when triturated with ether crystallized to a white powder (105 mg, 68%). RF (petroleum ether:diethyl ether, 1:1) 0.40. 1H NMR (CDCl3) δ 9.90 (s, 1H, O═C—H), 8.04 (s, 1H, ArH), 7.84 (d, 1H, J 8.4 Hz, ArH), 5.08 (s, 2H, CH2OPh), 4.34 (t, 2H, J 6.5 Hz, OCH2CH2Ph), 3.16 (t, 2H, J 6.5 Hz, OCH2CH2Ph).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].B.Cl>CO.N1C=CC=CC=1>[CH3:17][O:16][NH:18][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CON
Reactant: CC(=O)Nc1ccc(CCC=O)cc1
Agent: B
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CONCCCc1ccc(NC(C)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 3-(4-acetamidophenyl)propanal (96 mg, 0.50 mmol), methoxylamine hydrochloride (92 mg, 1.1 mmol), and pyridine (110 μL) in methanol (0.7 mL) is heated in a 70° C. oil bath for 18 hours and then allowed to cool to room temperature. Methanol (1 mL) is added and the mixture is cooled to 0° C. in an ice-water bath. Borane.pyridine complex (0.11 mL, 1.1 mmol) is added, followed by the dropwise addition of 10% aqueous hydrochloric acid. The mixture is allowed to warm to room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give N-[4-(3-methoxyamino-propyl)-phenyl]-acetamide.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=O)[O:14][C:15](O)([CH3:24])[C:16]=1[C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.COC(C)(C)C>C(O)CCC>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=[O:14])[NH:2][N:3]=[C:15]([CH3:24])[C:16]=1[C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC1(O)OC(=O)C(c2c(F)cccc2Cl)=C1c1ccc(Cl)nc1
Reactant: NN
Solvent: COC(C)(C)C
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (12 g) is added to a solution of 3-(2-chloro-6-fluoro-phenyl)-4-(6-chloro-pyridin-3-yl)-5-hydroxy-5-methyl-5H-furan-2-one (Compound No. II.a.1, 80 g) in 400 ml of 1-butanol and this mixture is heated for 7 h to 120° C. Subsequently, the mixture is poured into 400 ml of tert-butyl methyl ether. The resulting mixture is stirred for 30 min, then cooled to 0° C. and filtered. The solid remainder is washed with tert-butyl methyl ether to deliver 4-(2-chloro-6-fluoro-phenyl)-5-(6-chloro-pyridin-3-yl)-6-methyl-2H-pyridazin-3-one (Compound No. I.a.01) as colourless solid.