Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10]
Reactant: COC(COc1ccccc1C=O)OC
Reactant: Cc1cccc[n+]1C
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1ccccc1C=Cc1cccc[n+]1C)OC
Yield: 86.6 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethylpyridinium iodide and 1.50 g of o-(2,2-dimethoxyethoxy)benzaldehyde. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and then left to stand and cool off. The crystals which deposited consequently were collected and thoroughly washed with acetone. Consequently, there was obtained 2.36 g of 1-methyl-2-[o-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide which melted at 169°~173° C. This product showed the highest absorption at 353 nm (ε=1.78×104). The infrared absorption spectrum (KBr) showed peaks at 1630, 1610, 1595, 1567, 1515, 1500, 1450, 1280, 1248, 1130, 1065, 971, 780, 760 and 750 cm-1. The yield was 87%.
Reaction SMILES: [CH2:1]([C:3](C#N)([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:3]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:10][CH2:11]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(C#N)(CC)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Product: CCC(CC)(c1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 62 %

Procedure:
This was prepared according to the procedure described in Example 1 using 1-ethyl-1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-propyl cyanide and phenylmagnesium bromide. Yield was 62%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=O)[N:4]=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]1[N:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[C:29]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:30]([C:36]1[CH:41]=[CH:40][C:39]([C:42]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45][C:44]4([O:49][CH2:48][CH2:47][O:46]4)[CH2:43]3)=[CH:38][CH:37]=1)=[N:31]2)[NH2:25].C(O)(=O)C>CC(N(C)C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:35]3[C:26]([C:27]4[CH:28]=[C:29]([C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)[C:30]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45][C:44]7([O:49][CH2:48][CH2:47][O:46]7)[CH2:43]6)=[CH:38][CH:37]=5)=[N:31][C:32]=4[CH:33]=[CH:34]3)=[N:24][N:25]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CC7(C6)OCCO7)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (7.0 g, 56 mmol) in DMA (200 mL) was added EDC (11 g, 56 mmol) and HOBt (8.5 g, 56 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Then tert-butyl {2-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-10) (30 g, 56 mmol) was added and the reaction stirred at room temperature for an additional 1 hour at which time acetic acid (17 g, 280 mmol) was added and the reaction was stirred overnight at 80° C., The reaction mixture was cooled to room temperature, quenched with 1N NaOH, poured into saturated sodium bicarbonate, extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude residue was purified by column chromatography eluting with 10% methanol in DCM. The appropriate fractions were concentrated and the resulting solid was recrystallized from methanol to give tert-butyl (2-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]oct-2-yl)carbamate (1-11) as a white solid. MS (M+H)+: 630.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[CH:15]=[CH:14][C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[CH:15]=[CH:14][C:13]=1[CH:22]=[O:23]
Reactant: Cc1nc2c(Br)c(CO)ccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(Br)c(C=O)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (1.13 mL, 0.016 mol) was added to oxalyl chloride (0.84 mL, 0.0099 mol) in methylene chloride (37.10 mL) at −78° C. After 10 minutes, (4-bromo-2-methyl-1,3-benzothiazol-5-yl)methanol (1.71 g, 0.00662 mol) in methylene chloride (74 mL) was added and the resultant mixture was stirred at −78° C. for 30 minutes. Triethylamine (4.62 mL, 0.0331 mol) was then added and the mixture was stirred for 5 h and the temperature allowed to gradually warm up to room temperature. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. The resultant solid was used directly in next step (1.70 g, 100%). LCMS calculated for C9H7BrNOS(M+H)+: m/z=255.9; found: 255.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH:42]3[CH2:44][CH2:43]3)=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH:42]3[CH2:43][CH2:44]3)=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (255 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[O:34]1CCOCC1>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:34])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:15])=[CH:7]2
Reactant: C1COCCO1
Reactant: C=Cc1nc([C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)cc2cccc(Cl)c12
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347) (10.6 g, 23.3 mmol, 1.0 eq) in 1,4-dioxane (200 mL) and water (100 mL), OsO4 (50 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, NaIO4 (15 g, 69.9 mmol, 3.0 eq) was added, and then the mixture was stirred at RT for 16 h. The mixture reaction was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petro ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-l-formylisoquinolin-3-yl)ethylcarbamate (348).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:18]=2[CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH2:23][C:22]1[C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])=[C:18]([CH:25]=[C:26]([CH3:27])[CH3:28])[C:19]([CH3:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2c(N)ccc(C)c2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1c(C)ccc(N)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture (224) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 4 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the crude solid is purified by HPLC to give 48 mg brown solid (225).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:28])[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH:18]2[CH2:17][CH2:16][C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([N:14]([CH3:28])[CH3:13])[CH2:20][CH2:19]2)=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.12 g tryptamine and 1.52 g 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (12 ml) and 1,2-dichloroethane (40 ml) under argon. Glacial acetic acid (801 μl) and 1.92 g sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for four days at RT. For working up, the reaction mixture was concentrated and the residue was taken up in water (20 ml), two molar hydrochloric acid (5 ml) and ether (35 ml). The aqueous phase was separated off, washed with ether (2×15 ml), adjusted to pH 11 with sodium hydroxide solution and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The beige-brown residue obtained (2.0 g) was chromatographed over silica gel with methanol which contained 0.75 vol. % triethylamine. 553 mg of the nonpolar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 175-178° C.), from which the corresponding dihydrochloride was obtained with chlorotrimethylsilane in 2-butanone/acetone (20 ml/50 ml) (600 mg; m.p. 216-218° C.).
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]([NH2:18])([CH3:17])[CH3:16].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH:15]([CH3:17])[CH3:16])(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: CC(C)N
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: CC(C)NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
1.002 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.94 mL (10.9 mmol) isopropylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7]>>[Cl:1][Ge:2]([CH:6]([CH3:7])[C:5]([OH:9])=[O:8])([Cl:4])[Cl:3]
Reactant: C=CC(=O)O
Reactant: Cl[GeH](Cl)Cl
Product: CC(C(=O)O)[Ge](Cl)(Cl)Cl

Procedure:
Trichlorogermane (Cl3GeH) was added to acrylic acid (CH2CHCOOH) to obtain trichlorogermylpropionic acid (Cl3GeCH2CH2COOH). It was hydrolyzed to synthesize an organogermanium compound (1). In the same manner were synthesized organogermanium compounds (2) to (51).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[Na+]>C(O)(=O)C.C(O)(C)C>[CH3:22][C:21]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:1]=[CH:2][C:3]=2[NH:10][CH:9]=1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 23.4 %

Procedure:
N-acetyl serotonin was synthesized as follows. 100 mg (0.47 mmol) serotonin hydrochloride and 10 mL of pyridine were mixed in a 100 mL round-bottomed flask, and the solution was cooled to 0° C. under argon. Acetic anhydride (2.84 g, 28.4 mmol) was added slowly over 1 hr. After stirring at 0° C. for 20 hr the reaction was terminated by removing the volatile reagents under high vacuum. The remaining syrup was dissolved into 25 mL of methylene chloride and washed with 0.1 M HCl until the pH of the aqueous phase was less than 3. The organic phase was dried under anhydrous sodium sulfate, filtered and concentrated to yield a syrup. To this syrup was added 25 mL of aqueous isopropyl alcohol (50 wt%) and the solution was cooled to 0° C. Sodium hydroxide (1 mL of a 1.0 mM solution) was added and stirred at 0° C. for 4 hr. The solution was neutralized with acetic acid, concentrated and filtered through a short plug of silica gel with ether, concentrated and recrystallized from benzene/chloroform to yield 27 mg (0.11 mmol) of N-acetyl serotonin.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3)cccc2c1N
Yield: 46.9 %

Procedure:
Using method F, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.50 mmol) and 4-fluorophenylboronic acid (280 mg, 2.00 mmol) were reacted (reflux 24 hours) to afford the title compound (76 mg, 47% yield) as a white solid. 1H NMR (300 MHz, CDCl3)) δ8.56 (bm, 1H), 7.86 (dd, J=7.7 Hz, 1H), 7.65-7.80 (m, 4H), 7.19 (t, J=8.6 Hz, 2H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.67 (apparent sextet, J=7.4 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=325 (M+H) HPLC 1.74 min.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(4-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 6×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 146.2 mg (71%) of methyl 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (4-methoxyphenyl)boronic acid (350 g, 2.30 mol, 1.00 equiv) in 1,4-dioxane (3500 mL), methyl 4-bromo-3-methylbenzoate (527 g, 2.30 mol, 1.00 equiv), Pd(PPh3)4 (79.8 g, 69.06 mmol, 0.03 equiv), Cs2CO3 (1501 g, 4.60 mol, 2.00 equiv), water (850 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then cooled and quenched by the addition of 3000 mL of water. The resulting solution was extracted with 2×2000 mL of ethyl acetate. The organic layers were combined, washed with 1×2000 mL of brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50-1:20). This resulted in 471.6 g (crude) of methyl 4-(4-methoxyphenyl)-3-methylbenzoate as a red solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5](P(OCC)(OCC)=O)[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[H-].[Na+].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:44][CH:45]=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH2:1]([O:3][C:4](=[O:25])/[C:5](/[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:45]\[CH2:44][C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH3:2].[CH2:1]([O:3][C:4](=[O:25])/[C:5](/[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:45]/[CH2:44][C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCCOCc1ccccc1)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCOCc1ccccc1
Product: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-Benzyloxy-2-(diethoxyphosphoryl)-pentanoic acid ethyl ester (1.36 g, 3.65 mmol) in dry THF (5 mL) was added dropwise at 0° C. to a solution of sodium hydride (0.18 g, 7.46 mmol) in dry THF (3 mL). After stirring for 15 min tert-Butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (Example 1c) (1.0 g, 3.66 mmol) was added as a solution in dry THF (5 mL) dropwise to the reaction mixture. After stirring for 90 min at 0° C. the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL). After phase separation the aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate gradient) to give (Z)—(S)-2-(3-Benzyloxypropyl)-5-tert-butoxycarbonylamino-hex-2-enedioic acid 6-tert-butyl ester 1-ethyl ester and (E)-(S)-2-(3-Benzyloxypropyl)-5-tert-butoxycarbonylamino-hex-2-enedioic acid 6-tert-butyl ester 1-ethyl ester as a mixture of diastereomers.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.C(O)CCC>CO.C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 120 °C
Yield: 60.1 %

Procedure:
1-(1-Phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 4 (211 mg, 0.89 mmol) and 6-chloro-9H-purine (137 mg, 0.89 mmol) was placed in a sealed tube with n-butanol (1.7 mL) and the solution was heated to 120° C. for 48 h. The cooled suspension was diluted with MeOH/CHCl3 and the resulting solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product was further purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) and then triturated with EtOAc to afford racemic 102 as a cream solid (190 mg, 60%). LCMS: RT 2.99 min [M+H]+ 356.2. 1H NMR (DMSO, 400 MHz): δ 8.18-8.07 (2H, m), 7.94-7.85 (1H, m), 7.71-7.45 (7H, m), 7.27-7.17 (2H, m), 7.11-7.06 (1H, m), 5.52 (1H, br), 1.57 (3H, d, J=6.83 Hz)
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O)=[CH:5][CH:4]=1.[NH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:10](=[O:12])[NH:23][C:21](=[O:22])[NH:20][C:15]2=[O:17])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(C2C(=O)NC(=O)NC2=O)cc1

Procedure:
To a solution of sodium (184 mg) in 12 ml of ethanol are added 0.95 ml of diethyl 2-(4-Methylphenyl)malonate and 360 mg of urea, then the mixture is refluxed for 3 hours. A white solid separates, which is filtered and redissolved in 4 ml of water. The solution is acidified to pH=1-2 by adding 6 N hydrochloric acid. A white solid separates, which is collected by filtration, washed with 15 ml of water and dried under vacuum. 619 mg of the product are obtained, m.p. 271° C.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[C:8]1([S:5]([N:4]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[C:3]2[CH:9]=[CH:10][C:11]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH:12][C:2]=2[I:1])(=[O:7])=[O:6])[CH:11]=[CH:12][CH:2]=[CH:3][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccccc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 197.4 %

Procedure:
To a solution of the compound obtained in Example 8 (3) (2.20 g) in pyridine (7.4 ml), benzenesulfonyl chloride (1.57 g) was added and the mixture was stirred at 15 to 30° C. for 1 hour and at 60° C. for 1 hour. Further, to the mixture was added benzenesulfonyl chloride (1.57 g) and the mixture was stirred at 60° C. for 15 hours, and: then poured into a saturated aqueous ammonium chloride solution. The precipitates were filtered off, washed with water and ether successively and dried under reduced pressure to obtain 4.22 g of the desired products as a white crystal.