Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:16]2[CH2:17][CH2:18][N:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=3)[CH2:14][CH2:15]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2cccc(N3CCNCC3)n2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(6-phenyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12.[OH:20]O>C(O)(=O)C>[NH2:1][C:2]1[N+:7]([O-:20])=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21
Reactant: OO
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)[n+]([O-])cnc21
Reaction time: 72 h

Procedure:
A mixture of 2.0 grams of 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine dissolved in 100 millilitres of glacial acetic acid and 10 millilitres of 30% w/v hydrogen peroxide solution (100 volumes) was allowed to stand at room temperature for 3 days. The reaction mixture was evaporated to dryness and the solid product was collected, washed with acetic acid and dried. Recrystallisation from water gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidin-5-oxide, having melting point 285° C.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].NC(N)=O.[ClH:14]>[N+]([O-])(O)=O>[Cl:14][C@@H:2]([CH:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Cl
Agent: NC(N)=O
Solvent: O=[N+]([O-])O
Product: CCC(C)[C@H](Cl)C(=O)O
Temperature: 80 °C

Procedure:
To 20 g (0.150 moles) of L-(+)-isoleucine and 2 g of urea, 60 mL concentrated HCl and 30 mL concentrated HNO3 are added at room temperature. The mixture is subsequently heated for 1 hour at 80° C. and then for 1 hour at 50° C. on a water bath (complete dissolution of the acid with heavy foaming). After cooling, the solution is extracted with ether several times, the ether extract is washed with water and dried over calcium chloride, the solvent is distilled off in a rotary evaporator and the residue is fractionated under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].C([Mg]Cl)(C)C.C([Li])CCC.C(O)(=O)C[C:23](CC(O)=O)(C(O)=O)[OH:24]>C1COCC1.CN(C=O)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:23]=[O:24])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(C)cc1Br
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 1,4-dibromo-2,5-dimethylbenzene (5.0 g, 18.94 mmol, Aldrich) in anhydrous THF (20 mL) was cooled to about −10° C. Isopropyl magnesium chloride (3.95 mL, 2.0 M in THF, 7.9 mmol) was added. The mixture was allowed to stir at about −10° C. for about 0.25 h. Next n-butyl lithium (6.31 mL, 2.5 M in hexanes, 15.8 mmol) was added dropwise keeping the temperature at or below about 0° C. Once the addition was complete the reaction was stirred at about −10° C. for about 1 h. Next a solution of DMF in 10 mL anhydrous THF (20.52 mmol) was added dropwise keeping the temperature at or below about 0° C. The reaction was stirred at ambient temperature for about 3 hours. The reaction was poured into about 50 mL of about 5 M aqueous citric acid solution (exothermic) and stirred at room temperature for about 10 minutes. The layers were separated and the aqueous layer was extracted once with toluene (50 mL). The combined organic layers were washed with water (20 mL), then concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/petroleum ether 5:95) to give 4-bromo-2,5-dimethylbenzaldehyde (3.66 g, 17.18 mmol, 91%) as a pale crystalline solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.43 (3 H, s); 2.60 (3 H, s); 7.47 (1 H, s); 7.63 (1 H, s) 10.2 (1 H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:28])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33]>CCOC(C)=O>[Cl:37][C:36]([Cl:39])([Cl:38])[CH2:35][O:34][C:32](=[O:33])[NH:28][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of Intermediate 75a (739 mg, 1.811 mmol) in EtOAc (9 mL) and 1N sodium hydroxide solution (4.5 mL, 4.53 mmol) was added 2,2,2-trichloroethyl chloroformate (341 μL, 2.54 mmol), and the mixture stirred vigorously at RT for 1 h. The aqueous layer was extracted with EtOAc (2×20 mL), and then the combined organics dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (743 mg, 70%). LCMS (Method 4): Rt 4.69 min, m/z 582, 584, 586 [MH+].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:26]([CH2:27][CH2:28][CH3:29])=[O:30])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Yield: 84.4 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (example 9a) (0.200 g, 0.642 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (0.197 ml, 1.41 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added butyryl chloride (0.073 ml, 0.706 mmol) and the reaction was stirred at room temperature for 4 h. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (50 ml) and 0.5M aqueous citric acid (30 ml). The organic layer was separated, washed successively with saturated sodium bicarbonate solution (1×30 ml) and brine (1×30 ml), then dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether. The solid was collected by filtration to give the pure title compound as colourless crystals (0.187 g), m.p. 205°-206° C. δ (CDCl3, 360 MHz) 0.96 (3H, t, J=7.4 Hz, COCH2CH2CH3). 1.64-1.72 (3H, m, CHACHBHCCHD and COCH2CH2CH3), 2.17 (2H, t, J=7.4 Hz, COCH2CH2CH3), 2.68 (1H, dm, J=14.0 Hz, CHACHBHCCHD), 3.81 (3H, s, CO2CH3), 3.94 (1H, dd, J= 12.6 and 2.9 Hz, CHACHBHCCHD), 4.85 (1H, br.s, ArNH), 5.26 (1H, m, CHACHBHCCHDNHCO), 5.37 (1H, br.d, J=18 7 Hz, CHDNHCO), 6.56 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.73 (1H, d, J=2.0 Hz, 6-H or 8-H). m/e (CI+) 345 (100%, (M+I)+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >150° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.55-3.60 (m, 7H), 2.93 (s, 3H), 3.67 (brd, J=12.8 Hz, 2H), 4.56 (dd, J=9.6, 4.0 Hz, 1H), 4.64 (brd, J=6.5 Hz, 1H), 6.70-6.95 (m, 3H), 6.95-7.15 (m, 3H), 7.22 (d, J=2.1 Hz, 1H); MS (ES) m/z: 535.0 (MH+); HRMS Calcd. for C24H31N4O6S2 (MH+): 535.1685. Found: 535.1720.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[OH-].[Na+]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Cl)cc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (10.0 g, 43.1 mmol) and pyridine (43 mL) under nitrogen. To the resultant solution was added methanesulfonyl chloride (7.06 mL, 90.5 mmol) and the reaction was stirred at room temperature overnight. The following morning, the organics were concentrated in vacuo at 60° C., followed by hydrolysis of the bis-sulfonamide employing THF (65 mL) and sodium hydroxide (65 mL, 4.0 M). The resultant homogeneous solution was stirred at room temperature for 120 min. Upon completion of the hydrolysis, the THF was removed under reduced pressure and the pH of the aqueous layer was adjusted to 5-6 with 6 M HCl. The resultant solution was diluted with EtOAc and the organics were washed with 10% HCl and saturated sodium bicarbonate, dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to generate the desired methanesulfonamide: MS (ES) (M+H)+ expected 311.0, found 311.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.C(O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
26.5 g (0.11 mol) of methyl (2′-fluoro[1,1′-biphenyl]4-yl)acetate are introduced into 50 ml of ethanol and, at room temperature, a solution of 12.8 g (0.19 mol) of potassium hydroxide pellets in 25 ml of water is added. The mixture is then heated under reflux for 4 h. After cooling, the crude mixture is concentrated in vacuo, and the residue is dissolved in 100 ml of water and acidified with concentrated hydrochloric acid. The precipitate is filtered off and washed several times with water, and the solid is dried. Example VI is obtained in the form of white crystals.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:14]1([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([OH:24])=[O:5])=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To compound 19 (550 mg, 1.7 mmol) was added a solution of TFA in dichloromethane (95:5, v/v) (4.0 mL). The solution was stirred over a period of 4 h at room temperature under an argon atmosphere. The resulting solution was evaporated under reduced pressure and purified by FCC (CH2Cl2/MeOH, 95:5) to give 415 mg (89%) of title compound 20. 1H NMR (acetone-d6) δ: 2.00 and 2.35 (2m, 3.2 H and 0.8 H, 2×CH2 of proline), 3.66 and 3.74 (2m, 1.6H and 0.4H, CH2N of proline), 4.60 and 4.67 (m, 0.2H and 0.8H, NCHCO of proline), 7.57 (broad, m, 2×CH of naphthalene), 7.67 (d, J=8.4 Hz, 1×CH of naphthalene), 7.95 (broad, m, 2×CH of naphthalene), 8.14 (s, 1×CH of naphthalene). LRMS for C16H16NO3 [M+H]+: 270.0 m/z.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu](I)I>[CH3:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cnccc1Br
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnccc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 86.9 %

Procedure:
To a solution of 4-bromo-3-methyl pyridine hydrochloride (5.0 g, 24.0 mmol) in THF (degassed, 80 mL) was added copper iodide (450 mg, 2.40 mmol) and triethylamine (20.0 mL, 143.9 mmol). After degassing for 15 min, palladium tetrakis triphenylphosphine (830 mg, 0.72 mmol) and trimethylsilylacetylene (6.10 mL, 43.16 mmol) were added. The mixture was heated at 50° C. for 16 h then cooled to rt and filtered. The crude residue was purified via silica gel chromatography (EtOAc-Hexanes, 10%) to afford the title compound (3.95 g, 87%) as clear but dark oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and 1-methanesulfonyl-piperazine hydrochloride. Off-white powder. MS (m/z): 534.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[NH:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:15]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
2,4-Dichloro-7-methylquinazoline (2.0 g, 9.4 mmol) was suspended in 40 mL of dichloromethane under an N2 atmosphere and cooled to 0° C. (R)-tert-Butyl pyrrolidin-3-ylcarbamate (1.75 g, 9.4 mmol) was dissolved in a solution of 10 mL of dichloromethane and Et3N (2.62 mL, 18.8 mmol) and added dropwise to the above reaction mixture. The reaction was warmed to RT and stirred for 16 hours. The reaction was quenched with water, extracted with DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-tert-butyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (2.82 g, 83% yield). LC/MS: m/z 363.1 (M+H)+ at 3.26 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH:26](OCC)OCC)[C:9]([CH:11]([NH2:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C(C)(C)C)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH:40][C:41](=[O:51])[NH:42][CH:43]([CH2:48]C=C)[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)=O>[CH2:33]([NH:40][C:41]([N:42]1[CH:43]([CH3:48])[CH2:44][C:45](=[O:46])[N:24]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[C:9](=[O:10])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25][CH:26]12)=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C=CCC(CC(=O)O)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: CC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3ccccc3)CC2N1C(=O)NCc1ccccc1
Yield: 44.1 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amine (3.26 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 8-Benzyl-6-(4-hydroxy-benzyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.12 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.5-7.3 (m, 5H), 7.2 (d, J=7.01, 2H), 6.80 (m, 5H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.36 (m, 3H) MS ESI 513 (M+H), 535 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.B1(C=C)OB([CH:37]=[CH2:38])OB(C=C)O1.C1C=CN=CC=1>>[CH2:22]([O:21][C:20]1[C:15]2[S:14][C:12]3[N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:37]=[CH2:38])=[CH:3][CH:4]=4)[N:9]=[C:10]([CH3:30])[C:11]=3[C:16]=2[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1)[CH3:23]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1

Procedure:
The title substance was prepared by coupling 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine with 2,4,6-trivinylcyclotriboroxane-pyridine complex in analogy to Example 3. ESI-MS [m/z]: 433, melting point: 165-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Cl:33]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Cl:33])[C:22]([NH2:21])=[C:27]([Cl:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: NCCNc1cc(Cl)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-amino-3,5-dichlorophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Product: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1

Procedure:
Colorless oil prepared from 3,5-dimethyl-pyridine-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.53-1.60 (m, 4H), 2.27 (s, 6H), 2.65-2.75 (m, 2H), 3.10-3.16 (m, 2H), 3.83 (s, 2H), 4.76 (s, br, 1H), 7.24 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: C(O[Si](OCC)(OCC)CCC[O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[C:11]([OH:23])[CH:10]=1)C>C(O)C.O>[OH:23][C:11]1[CH:10]=[C:9]([OH:8])[CH:22]=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: CCO[Si](CCCOc1ccc(C(=O)c2ccccc2)c(O)c1)(OCC)OCC
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(O)cc1O

Procedure:
A mixture of 12.495 grams of recrystallized 4-allyloxy-2-hydroxybenzophenone (AHBP), 8.215 grams of triethoxysilane and 0.20 grams of the platinum substituted silica gel of Example 1 was heated at 90° C. It was found that the AHBP melted around 55° C. The reaction mixture became yellow and homogeneous. The temperature of the reaction mixture then quickly rose to 130° C. and then dropped to 90° C. After heating the mixture of an additional hour at about 90° C., the mixture was allowed to cool to 23° C., diluted with 50 ml of hexane and then filtered. The platinum substituted silica gel was recovered as a free-flowing tan powder. The filtrate was concentrated on a rotary evaporator and 20 grams of a yellow oil, a quantitative yield of product was recovered. Based on method of preparation and reverse phase TLC, 4/1;ethanol/water, the product was 4-(3'-triethoxysilylpropoxy)-2-hydroxybenzophenone (SHBP). A trace amownt of 2,4-dihydroxybenzophenone was also obtained. The 1H NMR spectrum of the SHBP was found to be identical to a spectrum of SHBP prepared from AHBP and triethoxysilane using a platinum catalyst shown by Karstedt, U.S. Pat. No. 3,775,452.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCOCC1.CCOC(C)=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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:6]1[O:7][CH:8]=[CH:9][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(-c2ncco2)nc1
Yield: 67 %

Procedure:
2-(Tributylstannyl)oxazole (1.00 g, 2.79 mmol), (Ph3P)4Pd (0.1 equiv), and 2-bromopyridine (2 equiv) were dissolved in anhydrous 1,4-dioxane (15 mL) and the mixture was warmed at reflux for 24 h under Ar. The mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude product that was purified by flash chromatography (SiO2, 10-60% EtOAc-hexanes) to yield the title compound (275 mg, 67%) as a light yellow oil: 1H NMR (CDCl3, 500 MHz) δ 8.63 (m, 1H), 8.04 (d, 1H, J=7.5 Hz), 7.73-7.70 (m, 2H), 7.26-7.22 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 161.0, 150.2, 146.4, 140.1, 137.3, 129.1, 125.0, 122.3.