Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH3:8][N:9]1[C:14](=[O:15])[N:13]2[CH:16]=[N:17][C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[N:11]=[N:10]1>C(#N)C>[NH:20]=[C:19]([C:18]1[N:17]=[CH:16][N:13]2[C:14](=[O:15])[N:9]([CH3:8])[N:10]=[N:11][C:12]=12)[S:21][CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5]
Reactant: Cn1nnc2c(C(N)=S)ncn2c1=O
Reactant: O=C(O)C(=O)CBr
Solvent: CC#N
Product: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromopyruvic acid (1.388 g; 8.3 mmol) in dry acetonitrile (20 mL) was added 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (1.000 g; 4.8 mmol). The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was washed with DCM (3×15 mL) and diethyl ether (2×20 mL) and the pale yellow solid (1.20 g; 84%) was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:15]=[N+:16]=[N-:17].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)CC>[N:15]([CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:16]=[N-:17]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCO[Si](CCCN=[N+]=[N-])(OCC)OCC
Yield: 80 %

Procedure:
To a solution of 3-chloropropyltriethoxysilane (2.31 g, 9.6 mmol) and tetrabutylamonium iodide (0.020 g, 0.05 mmol) in butanone (25 mL) was added sodium azide (3.120 g, 48 mmol) and the reaction mixture was heated under reflux for 50 h. Filtration over celite was followed by evaporation of the solvent under vacuum. The residue was dissolved in dichloromethane (150 mL) and then washed with water (2 times 20 mL). The organic phase was dried (NaSO4) and evaporated to give the desired product (1.9 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20].[Cl-].[NH4+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([OH:8])[CH:3]=1
Reactant: C=O
Reactant: Oc1cccc(I)c1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1ccc(I)cc1O
Yield: 160.1 %

Procedure:
To a solution of 3-iodophenol (3.00 g, 13.6 mmol) in acetonitrile (50 mL) was added magnesium chloride (3.89 g, 40.9 mmol), triethylamine (7.6 mL, 55 mmol), and paraformaldehyde (1.64 g, 55 mmol). The reaction mixture was refluxed overnight, then neutralized with saturated aqueous ammonium chloride. The resultant red precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The precipitate was dissolved in methanol and added to the combined organic extracts, which were then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide an orange solid (5.4 g) as the crude product. This material was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)C(C)C)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized in Example A67(2) and isobutyryl chloride (1.56 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (1.933 g, 66%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[C:3]1=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(C=C2Cc3ccccc3C2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C=C2C(=O)c3ccccc3C2Br)cc1

Procedure:
4-(1-Oxoindan-2-ylidenemethyl)benzonitrile (2.18 g, 8.9 mmol) was dissolved in carbon tetrachloride (40 mL). N-bromosuccinimide (1.58 g, 8.9 mmol) and benzoyl peroxide (100 mg) were added in one portion. Reaction mixture was reflux for 9 h, cooled down; precipitate was filtered off and washed with diethyl ether (10×30 mL) for removal of N-hydroxysuccinimide Precipitate was dried under vacuum, provided pure 15a.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:39])([CH3:30])[CH3:29]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1ccccc1NC(N)=S
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropylphenyl)thiourea isolated as a white solid (0.033 g, 11%): 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.14 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.94 (m, 2H), 7.68-7.57 (m, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dq, J=7.8, 1.5 Hz, 2H), 7.34 (dd, J=7.8, 1.6 Hz, 1H), 7.26 (td, J=7.5, 1.5 Hz, 1H), 7.20 (td, J=7.5, 1.6 Hz, 1H), 7.03 (t, J=5.7 Hz, 1H), 3.47 (q, J=6.6 Hz, 2H), 2.98 (p, J=6.9 Hz, 1H), 2.89 (t, J=6.9 Hz, 2H), 1.15 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][CH:8]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:19]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cccc(CCCCCCC(=O)O)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1cccc(OC)c1
Temperature: 0 °C

Procedure:
An anhydrous solution of methanol:toluene (2:5) (10.5 mL) was used to solubilize 7-(3-methoxyphenyl)heptanoic acid (0.159 g, 0.673 mmol) under an atmosphere of argon and the solution was then cooled to 0° C. Stirring was initiated and a 2 M solution of TMSCHN2 (in hexanes) (0.740 mL, 1.48 mmol) was added dropwise to the reaction solution. The yellow solution was allowed to stir for 30 minutes at room temperature before again being cooled to 0° C. The reaction was quenched with the dropwise addition of acetic acid until the characteristic yellow color of diazomethane dissipated. The solvent was removed under vacuum and the resultant suspension taken in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate then brine and dried over sodium sulfate. The solvent was removed under vacuum and the target product was purified as a light yellow oil (92%, 0.139 g) using flash column chromatography (silica) with a 10% ethyl acetate:hexanes mobile phase: 1H NMR (500 MHz, CDCl3) δ 7.19 (t, 1H), 6.74 (q, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 2.59 (t, 2H), 2.31 (t, 2H), 1.63 (m, 4H), 1.36 (m, 4H); 13C NMR (500 MHz, CDCl3) δ 174.17, 159.60, 144.31, 129.17, 120.82, 114.17, 110.86, 55.06, 51.41, 35.93, 34.05, 31.17, 29.01, 28.91, 24.89.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)#[CH:7].[C:20](=[O:22])=[O:21].Cl>CCCCCC.C1COCC1>[N:13]1([CH2:12][C:11]2[CH:18]=[CH:19][C:8]([C:6]#[C:7][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C#Cc1ccc(CN2CCCC2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Reaction time: 1 h

Procedure:
5.98 mL (14.85 mmol) of a 1.6M butyllithium solution in n-hexane is added dropwise to a solution of 2.3 g (12.41 mmol) of 1-(4-ethynylbenzyl)pyrrolidine in 50 mL of THF at −78° C. and stirred for 1 hour at this temperature. Then dry ice is added to the reaction mixture. Then the reaction mixture is allowed to come up to ambient temperature and stirred for 14 hours. The reaction mixture is combined with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is separated off and dried over sodium sulfate. The sodium sulfate is separated off and the solvent is removed. Yield: 0.3 g (10.5% of theory); C14H15NO2 (M=229.28); calc.: molecular ion peak (M+H)+: 230; found: molecular ion peak (M+H)+: 230; Rf value: 0.15 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: OCCCN[C:6](=O)[C@H:7]([C:9]([CH2:12][OH:13])(C)C)[OH:8].CN(C1C=CC=CN=1)C.C([O:27][C:28](=[O:30])[CH3:29])(=O)C>>[CH3:6][C:7]([CH2:9][C:12]([CH2:29][C:28]([OH:27])=[O:30])=[O:13])=[O:8]
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 80 °C
Reaction time: 9 h

Procedure:
D-panthenol (88 grams, 0.424 moles) and polymer bound dimethylaminopyridine (2 grams) were added to a flask. Acetic anhydride (144.4 grams, 3.3 moles) was slowly added to the stirring mixture, and the resultant exotherm was controlled when the temperature reached 80° C. The mixture was heated at 80° C. and stirred for 9 hours. The flask was then fitted for vacuum distillation, and the acetic acid was removed under reduced pressure to a concentration of about 4% w/w. The catalyst (P-DMAP) was filtered out from the reaction mixture. The solution was treated with a 50% w/w solution of sodium hydroxide in a volume sufficient to neutralize the residual acetic acid, and the resultant solids of sodium acetate were removed by filtration. The residual water was then removed under vacuum to afford about 80% of the desired product, D-panthenyl triacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH:31](OS(C)(=O)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)n1nc(C(=O)OC)c(OCc2ccccc2)c1C(=O)OC
Temperature: 50 °C

Procedure:
To a solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (4.0 g, 13.8 mmol) and ethyl 3-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyloxy)propanoate (4.29 g, 13.8 mmol) in anhydrous CH3CN (200 mL) was added Cs2CO3 (4.49 g, 13.8 mmol). The mixture was heated to 50° C. overnight, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to afford the title product as a pale yellow oil. ES MS (M+H)=506.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]=O)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:17][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Additionally, 2-phenylquinoline-7-carbaldehyde could be prepared as follows: To a solution of(2-phenylquinolin-7-yl)methanol (75 mg, 0.319 mmol) in chloroform (1 mL) was added MnO2 (277 mg, 3.19 mmol). The mixture was stirred at rt for 20 h and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography. (1% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz) δ 7.50-7.59 (m, 3H), 7.95 (d, J=8.8 Hz, 1H), 8.04 (dd, J=2.4, 8.8 Hz, 2H), 8.19-8.22 (m, 2H), 8.31 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 10.26 (s, 1H). MS (ES+): m/z 234 [MH+]. HPLC: tR=3.59 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([OH:18])[CH2:20]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: O[C@@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@@H](O)C2)c1S(C)(=O)=O
Yield: 59.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (R)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extracted with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 209 mg (60%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)C1C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[Cl:39].C([O-])([O-])=O.[Na+].[Na+].ClCCl>CO.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>[Cl:32][C:33]1[CH:34]=[C:35]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][C:12]2[N:11]3[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[C:27](=[O:28])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1ccc(Cl)c(Cl)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: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(Cl)c(Cl)c3)nc(=O)c(O)c2C1=O
Reaction time: 8 h
Yield: 15.2 %

Procedure:
9-Benzyloxy-6-(2-bromobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (71) (0.1 g, 207 μmol, Eq: 1.00, ˜40% pure), 3,4-dichlorophenylboronic acid (47.5 mg, 249 μmol, Eq: 1.2), Na2CO3 (65.9 mg, 622 μmol, Eq: 3) and tetrakis(triphenylphosphine)palladium (0) (24.0 mg, 20.7 μmol, Eq: 0.1) were stirred in methanol (0.9 ml)/dichloromethane (300 μl) in the microwave at 115° C. for 30 minutes. The reaction mixture stood at room temperature overnight. The supernatant was pipetted off, concentrated and purified by SiO2 flash chromatography (4 g SiO2, dichloromethane/methanol 0-5% methanol) to afford 6-(3′,4′-dichloro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (72) (0.016 g, 31.4 μmol, 15.2% yield, 90% pure) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccccc1-n1cc(C)c(C=O)n1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1-n1cc(C)c(C(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution (10 mL) of 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.97 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (5.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.56 g, 40%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:28]1CCOCC1>[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Cc2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl
Reactant: C1COCCO1
Agent: [Mn+4]
Agent: [O-2]
Product: COC(=O)c1cc(C(=O)c2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl

Procedure:
1.29 g (3.20 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazole-5-carboxylate were dissolved in 80 ml of dioxane, 16.72 g (192 mmol) of manganese(IV) oxide were added and the mixture was stirred at reflux for 12 h. The mixture was filtered off with suction and the filtrate was freed from the solvent. The desired product was obtained by chromatographic purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C@H:16]([CH3:31])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[C:24](=[O:30])[NH:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:32])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[CH:26]1([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:17](=[O:18])[C@@H:16]([CH3:31])[O:15][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH3:32])=[CH:10][CH:11]=3)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)=[O:30])[CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(O[C@H](C)C(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.30 g 4-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid methyl ester in 14 ml THF were added 14.3 ml aqueous NaOH (1 M) and the reaction mixture was stirred for 4 h at RT. The reaction mixture was acidified with 15 ml 1 M HCl, concentrated to a volume of 25 ml and extracted with DCM to give the crude product after evaporation of the solvent. Yield: 5.00 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]=[N+:12]=[N-:13])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of 4-methoxybenzyl chloride 1000 (51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solid sodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and the resulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were washed with H2O (2×200 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2 g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil, which by HPLC and 1H NMR was found to be essentially pure and was directly used in the subsequent reaction without further purifications. For 4-methoxybenzyl azide 1001: 1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, ArOCH3), 4.29 (s, 2H, Ar—CH2), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=7.8 Hz).
Reaction SMILES: CI.[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[NH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[N:29]([CH3:33])[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc2ncc3c(c2n1)NC(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 123.6 %

Procedure:
Methyl iodide (10.5 μL, 0.17 mmol, 1.0 eq) is added at room temperature to a stirred solution of [6-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester (70 mg, 0.17 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by cesium carbonate (55 mg, 0.17 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [6-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an orange viscous oil (89 mg, 75% yield) that is directly engaged in the next step.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)([O:3]C)=[O:2].[OH-].[K+].C(O)C.Cl>O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1

Procedure:
A solution of 5 g. of ethyl 4-(15-carbomethoxypentadecylamino)benzoate and 0.8 g. of potassium hydroxide in 50 ml. of 95% ethanol is stirred at 50° C. for 10 hours, diluted with 100 ml. of water and acidified with concentrated hydrochloric acid. The solid is collected by filtration, dried, and recrystallized from toluene to yield ethyl 4-(15-carboxypentadecylamino)benzoate as a white solid.