Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
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: O
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 0.087 mol) in 150 ml 1,2-dimethoxyethane is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 0.096 mol) and tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.00174 mol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with 200 ml of ethyl acetate. The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH:10]([CH2:21][CH2:22][C:23]([CH:25]([OH:37])[C@H:26]1[O:32][C@:30]([CH3:33])([OH:31])[C@H:29]([OH:34])[C@@H:28]([OH:35])[C@@H:27]1[OH:36])=[O:24])[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[CH3:33][C@@:30]1([O:32][C@H:26]([CH:25]([C:23]([CH2:22][CH2:21][CH:10]([C:9]([OH:38])=[O:8])[C:11]([OH:13])=[O:12])=[O:24])[OH:37])[C@@H:27]([OH:36])[C@H:28]([OH:35])[C@H:29]1[OH:34])[OH:31]
Reactant: C[C@]1(O)O[C@H](C(O)C(=O)CCC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@]1(O)O[C@H](C(O)C(=O)CCC(C(=O)O)C(=O)O)[C@@H](O)[C@H](O)[C@H]1O
Yield: 17.5 %

Procedure:
A solution of compound (69) (250 mg) in EtOH (20 mL) and AcOH (5 mL) was stirred under a hydrogen atmosphere (balloon) in the presence of 10% Pd/C (25 mg) for 4 h. After removal of the catalyst by filtration through celite, the filtrate was purified by preparative HPLC to provide the title compound (70) (29 mg) as a white solid. 1H NMR (CD3OD, 400 MHz): 4.65 (d, 1H), 4.40 (dd, 1H), 4.21 (dd, 1H), 3.65–3.76 (m, 1H), 3.58 (t, 1H), 3.36–3.50 (m, 1H), 3.39 (s, 3H), 3.25–3.35 (m, 1H), 2.46 (t, 2H), 2.14 (q, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH2:8][CH2:7]2.C1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c2c(c1)CCCN2
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
8-Fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol) was stirred in borane-THF complex, 1M in THF (140 ml, 140 mmol). The solution was heated to 60° C. and stirred overnight. The mixture was then cooled in an ice bath and quenched via addition of methanol (30 mL). The quenched solution was concentrated, then dissolved in methanol and refluxed for 1 h. The solution was then concentrated onto silica gel and chromatographed using 5-30% ethyl acetate in hexanes to give the desired 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (4.34 g, 22.12 mmol, 79% yield). 1H NMR (DMSO-d6) δ 7.77-7.71 (m, 1H), 7.73 (m, 1H), 7.31 (brs, 1H), 3.35-3.28 (m, 2H), 2.77 (t, J=6.2 Hz, 2H), 1.85-1.77 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]1)=O.[Cl-].[NH4+]>C1COCC1>[C:24]([O:23][C:21]([N:13]1[CH2:14][CH2:15][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]([CH2:9][OH:8])[CH2:12]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(CO)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.7 %

Procedure:
To a suspension of lithium aluminium hydride (0.75 g) in THF (30 mL) was added a solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.2 g) in THF (20 mL) at 0° C. The reaction mixture was subsequently warmed to room temperature. After stirring for 2.5 h, ammonium chloride solution (5 mL) was added to the reaction mixture, which was then filtered through celite, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (1.13 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.[C:13]1([C@@H:19]([N@:21]2[CH2:23][CH:22]2[CH:24]=[O:25])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[C:2]1([C@H:24]([CH:22]2[CH2:23][N@@:21]2[C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:20])[OH:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccccc1)[N@]1CC1C=O
Reactant: Brc1ccccc1
Agent: C[C@@H](c1ccccc1)[N@@]1CC1[C@H](O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccccc1)[N@]1CC1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of bromobenzene (4.93 g, 31.4 mmol) in THF 125 mL under nitrogen at −78° was added t-BuLi (1.7 M in pentane, 50 mL). The mixture was stirred for 0.5 h at room temperature. The mixture was cooled down to −78° C. and a solution of (R)-1-((S)-1-phenylethyl)aziridine-2-carbaldehyde EBE 06048 (2.5 g, 14.3 mmol) in THF (16.7 mL) at −78° C. was added dropwise. The reaction mixture was treated with H2O (20 mL), the organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a residue that was purified by column chromatography using a gradient of 0-20% [v/v] EtOAc in cyclohexane to give (R)-phenyl((R)-1-((S)-1-phenylethyl)aziridin-2-yl)methanol EBE 06066 (3.13 g, 86% yield).
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([CH2:20][N:6]2[CH2:7][CH2:8][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(Cc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
Sodium borohydride (500 mg) was added to a mixture of 1.6 g of ethyl 1-piperazinecarboxylate, 1.3 g of p-tolualdehyde and 30 ml of ethanol, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 50 ml of water was added, and the resultant mixture was extracted with ethyl acetate. The ethyl acetate extract was then extracted with diluted hydrochloric acid. The diluted hydrochloric acid extract was washed with ethyl acetate, made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous potassium carbonate and concentrated under reduced pressure to give 0.8 g of ethyl 4-p-tolylmethyl-1-piperazinecarboxylate as an oil. This was deprived of the carboethoxy group by the method described in Reference Example 38 to give 0.36 g of 1-ptolylmethylpiperazine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].Cl[CH2:19][CH2:20][CH:21]([OH:30])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:23]([CH2:22][CH:21]([OH:30])[CH2:20][CH2:19][N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:10][CH:9]=2)[CH2:16][CH2:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Product: CCOC(=O)c1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-(1-piperazinyl)benzoic acid ethyl ester and 4-chloro-1-phenoxy-2-butanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].[Na]>C(O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccncc2)CCN(C)C1
Yield: 2.9 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (100 mg, 0.5 mmol), 4-vinylpyridine (120 mg, 1.14 mmol) and sodium (5 mg, 0.21 g atom) in ethanol (1 mL) at 120° C. for 16 h to obtain 4.5 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1([C:30](OC)=[O:31])[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[C:18]([NH:19][CH2:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[OH:22])[C:8]=2[O:7]1)[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:5].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C(O)C>[ClH:29].[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:4][CH2:6][O:7][CH3:8])[C:30]([C:6]1([C:4]([OH:3])=[O:5])[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[C:18]([NH:19][CH2:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[OH:22])[C:8]=2[O:7]1)[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:31]
Reactant: COCCN
Reactant: COC(=O)C1(C(=O)OC)Oc2cc3c(c(NCC(O)c4cccc(Cl)c4)c2O1)CCCC3
Agent: Cl
Solvent: CCO
Product: COCCN(CCOC)C(=O)C1(C(=O)O)Oc2cc3c(c(NCC(O)c4cccc(Cl)c4)c2O1)CCCC3

Procedure:
A solution of product from Example 20 in ethyl alcohol is stirred at room temperature for 20 hours with an excess of methoxyethylamine. The reaction mixture is evaporated in vacuo and combined with a sodium carbonate solution and diethyl ether. The layers are separated and the diethyl ether layer is dried over sodium sulfate and filtered. Gaseous hydrogen chloride is bubbled into the filtered diethyl ether solution and the desired product is collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Yield: 43.8 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopentane (0.130 mL, 1.0 mmol) to give the title compound (0.072 g) as a white solid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl.[CH3:17]O>>[C:1]([O:11][CH3:17])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
To a round-bottomed flask, trans-cinnamic acid (7 g, 47.25 mmol) and MeOH(70 mL) were added. POCl3 (0.43 mL, 4.73 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH solution. The mixture was extracted by EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum (7.1 g, 80˜95%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]1[C:19]([Cl:24])=[N:20][CH:21]=[CH:22][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:19]1[C:18]([CH2:17][N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Clc1ncccc1CBr
Reactant: c1cncc(Nc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncccc1CN(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
To a solution of N-pyridin-3-ylpyridin-3-amine (510 mg, 3 mmol) in anhydrous DMF (4.5 mL) was added 60% sodium hydride/mineral oil (169 mg, 4.2 mmol). After stirring at ambient temperature for 15 min., 3-(bromomethyl)-2-chloropyridine (677 mg, 3.28 mmol) (preparation described in U.S. Pat. No. 5,739,326) was added neat and the action was stirred for ˜2 hours. The reaction was diluted with ethyl acetate, washed with NaHCO3 solution, then water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by silica gel chromato-graphy eluting with a 20-90% acetonelhexane gradient to give the purified product which upon trituration with diethyl ether gave the title compound as a tan solid (684 mg, 77% yield). 1H-NMR (500 MHz , CDCl3): δ 8.40 (2H, d, J=2.7 Hz), 8.34 (1H, d, J=4.6 Hz), 8.30 (2H, d, J=4.6 Hz), 7.69 (1H, d, J=7.8 Hz), 7.33-7.35 (2H, br d, J=˜8.3 Hz), 7.20-7.26 (4H, m), 5.04 (2H, s). m/e (m+1): 297.0
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ccccc1S
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 140 °C

Procedure:
44.6 g (0.34 mol) of 4-cyanobenzaldehyde and 54.4 g (0.64 mol) of o-aminobenzenethiol were dissolved in 300 ml of dimethyl sulfoxide, and the temperature of the solution was raised to 140° C. The produced water and the dimethyl sulfoxide were distilled off. After heating for one hr, the residue was cooled, water was added thereto, and the resultant precipitate was collected by filtration and washed with ethanol. The crude crystal thus obtained was recrystallized from ethyl acetate to give 2-(4'-cyanophenyl)benzothiazole. 22.4 g (0.095 mol) of the compound was dissolved in 250 ml of acetic acid, and 18.6 g (0.116 mol) of bromine was dropwise added thereto. As soon as bromine was added, a yellow bromine adduct was produced. Subsequently, 150 ml of water was added, and the mixture was stirred at 80° C. for 2 hr. It was then cooled, and the resultant precipitate was collected by filtration and washed with ethanol. The crude product thus obtained was recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[NH2:2].[OH:12]O.O>CS(O)(=O)=O>[C:1]([NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([O:10][OH:12])=[O:9])(=[O:3])[NH2:2]
Reactant: OO
Reactant: NC(=O)NC(=O)CCC(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Product: NC(=O)NC(=O)CCC(=O)OO
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
80 g (0.5 mol) of N-carbamoylsuccinamic acid are dissolved in 160 g of methanesulfonic acid and the solution is cooled to 15° C. 60 g (1.5 mol) of hydrogen peroxide (85% strength by weight) are added dropwise with cooling at such a rate that the internal temperature can be maintained between 15° and 20° C. The reaction mixture is stirred at 20° C. for 10 minutes, then cooled to 10° C. and admixed with water added dropwise with cooling. The precipitated peroxycarboxylic acid is filtered off with suction, washed free of mineral acid with water and dried at 40° C. under an aspirator vacuum.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:46][CH2:45][C:17]([CH3:47])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[CH2:30][N:31]([CH:41]2[CH2:43][CH2:42]2)[CH2:32]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:47])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[CH2:30][N:31]([CH:41]2[CH2:43][CH2:42]2)[CH2:32]3)[CH2:45][CH2:46]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1CN(C1CC1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1CN(C1CC1)C3
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{11-cyclopropyl-16-fluoro-4,25-dimethyl-24-oxa-1,5,7,8,11-pentaazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (35 mg, 0.054 mmol) and NaOH (2.154 mg, 0.054 mmol) in EtOH (3 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to isolate (2S)-2-(tert-butoxy)-2-{11-cyclopropyl-16-fluoro-4,25-dimethyl-24-oxa-1,5,7,8,11-pentaazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acid (25.2 mg, 0.040 mmol, 73.7% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.18 (t, J=7.2 Hz, 1H), 6.98 (d, J=9.9 Hz, 1H), 6.85 (t, J=7.7 Hz, 1H), 6.43 (s, 1H), 5.75 (s, 1H), 4.39 (t, J=11.9 Hz, 1H), 3.89 (d, J=9.9 Hz, 1H), 3.65-3.54 (m, 2H), 3.30 (d, J=15.0 Hz, 2H), 3.17 (s, 2H), 2.87-2.77 (m, 1H), 2.73-2.63 (m, 2H), 2.51-2.45 (m, 4H), 1.89-1.42 (m, 11H), 1.16 (br. s., 12H), 0.33 (br. s., 1H), 0.24 (br. s., 1H), 0.13 (br. s., 1H), −0.06 (br. s., 1H). LCMS (M+1)=622.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:59]2[O:55][N:56]=[CH:57][CH:58]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccno2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as starting materials in 59% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.50 (d, 2H), 9.16 (s, 1H), 8.83 (s, 1H), 8.40 (s, 2H), 8.33 (s, 1H), 7.78 (s, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.00 (s, 1H), 4.52 (m, 1H), 3.88 (m, 1H), 3.32 (m, 1H), 3.03 (s, 4H), 2.42 (m, 2H), 2.21 (m, 1H), 1.93 (m, 2H), 1.39 (m, 2H). LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](/[CH:13]=[C:19]2/[C:18](=[O:20])[NH:17][C:16](=[O:21])[S:15]/2)=[CH:10][CH:9]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Product: O=C1NC(=O)/C(=C/c2ccc(-c3ccccc3Cl)o2)S1

Procedure:
The titled compound was prepared by the condensation of 5-(5-(2-chloro-phenyl)furan-2-aldehyde (1.0 g) with 2,4-thiazolidinedione (0.68 g) using the procedure described in Step B of EXAMPLE 1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([CH3:19])=[CH:15][N:14]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:27])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([CH3:19])=[CH:15][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:27]
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CCCNC(=O)OC(C)(C)C)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CCCN)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-methyl-1H-pyrimidine-2,4-dione (1.9 g, 4.5 mmol) in ethyl acetate (200 mL) at −78° C. was added HCl (g) for 5 min. The reaction was warmed to ambient temperature, the excess HCl removed by bubbling through nitrogen gas and then the reaction concentrated to provide the hydrochloride salt of 3-(3-aminopropyl)-1-benzyl-5-methyl-1H-pyrimidine-2,4-dione as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[OH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][OH:26])[CH2:29]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OCC1CCCNC1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCCC(CO)C2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 3-hydroxymethylpiperidine (1.29 g) and 2-butanone (10 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The organic layer was washed with 100 ml of water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(3-hydroxymethyl-1-piperidinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (102 mg, 27%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.