Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=2[CH2:29][CH2:28]1>>[Cl:22][C:5]1[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: Fc1cccc(OC2CCOC2)c1Oc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Oc4c(F)cccc4OC4CCOC4)n3)cc2CC1

Procedure:
Title compound was prepared from 2,5-Dichloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidine and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 1d. Title compound was isolated as a white solid. HPLC purity=99%, LCMS=531.32 (M+H), 1HNMR (CDCl3, 400 MHz) δ 9.00 (bs, 1H), 8.24 (s, 1H), 7.28-7.16 (m, 3H), 7.16-7.14 (m, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.29 (bs, 1H), 4.97 (s, 1H), 3.86-3.78 (m, 8H), 3.38-3.32 (m, 7H), 2.85-2.81 (m, 3H), 2.60-2.55 (m, 1H), 2.09-1.95 (m, 2H).
Reaction SMILES: [CH:1](=[N:8][C@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:25]([CH2:28][C:29](Cl)=[O:30])=[N+:26]=[N-:27]>C(Cl)Cl>[C:14]([O:13][C:11]([C@@H:9]([N:8]1[C@@H:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:28]([N:25]=[N+:26]=[N-:27])[C:29]1=[O:30])[CH3:10])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccccc1
Reaction time: 14 h
Yield: 41.1 %

Procedure:
To 75 ml. of a solution of N-benzylidene-1(S)-t-butoxycarbonylethylamine (5.07 g., 21.7 mmol) and triethylamine (4.84 g., 47.8 mmol) in methylene chloride, there was gradually added dropwise 75 ml. of a solution of azidoacetyl chloride (5.19 g., 43.5 mmol) in methylene chloride at -78° C. After stirring at -78° C. to room temperature for 14 hours, the reaction mixture was washed with water and then with a saturated saline solution, followed by drying over anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was subjected to silica gel column chromatography, using hexane-ethyl acetate (3:1) as an eluent, to give 1-(1(S)-t-butoxycarbonylethyl)-3(S)-azido-4(R)-azetidin-2-one (2.68 g., yield: 39%) and 1-(1(S)-t-butoxycarbonylethyl)-3(R)-azido-4(S)-phenylazetidin-2-one (2.82 g., yield: 41%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].O[N:14]1[C:19](=[O:20])[CH2:18][CH2:17][C:15]1=[O:16]>C(Cl)(Cl)Cl>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([O:5][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][C:15]1=[O:16])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
Boc-Gly-OH (1.54 g, 8.82 mmol) was put in a 500-mL eggplant flask and dissolved in distilled CHCl3. Then, DCU (2.18 g, 10.6 mmol) and HOSu (1.21 g, 10.6 mmol) were added thereto, and the stirring was started under cooling. After having been left standing overnight, the completion of the reaction was confirmed with TLC and the resultant was concentrated. After filtered, DCUrea was dissolved in AcOEt and the reprecipitated DCUrea was filtered. After that, the filtrate was concentrated and recrystallized with AcOEt-distilled Et2O twice, whereby Boc-Gly-OSu was obtained. The yield was 1.74 g (63.9%). 1H NMR (CDCl3, 300 MHz): 5.04 (1H, Boc-Gly NH); 4.27, 4.23 (2H, Gly αCH2); 2.79 (4H, OSu); 1.40 (9H, Boc t-Bu).
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[C:13]([I:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:6]=1[C:7](O)=[O:8]>>[Cl:15][C:11]1[CH:10]=[C:6]2[C:5](=[C:13]([I:14])[CH:12]=1)[N:4]=[CH:1][NH:3][C:7]2=[O:8]
Reactant: Nc1c(I)cc(Cl)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2c(I)cc(Cl)cc12
Temperature: 130 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a round bottom flask was added formamide (4 equiv., 13.5 mmol, 605 mg) and 2-amino-5-chloro-3-iodo-benzoic acid (1000 mg, 3.4 mmol). The reaction was capped and shaken at 130° C. for 72 h. The reaction was cooled to room temperature, then the precipitate was collected by filtration and washed 3× with water. The precipitate was dried under vacuum, yielding 881 mg of 6-chloro-8-iodo-3H-quinazolin-4-one as a purple solid. 1H NMR (400 MHz, DMSO) δ 12.66-12.49 (s, 1H), 8.40-8.37 (d, J=2.4 Hz, 1H), 8.24-8.21 (s, 1H), 8.09-8.05 (d, J=2.4 Hz, 1H). LCMS M/Z (M+H)=307.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](=O)[CH3:24])=[C:15]1Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].O>CO.CCOC(C)=O>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:23]([CH3:24])=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1sc2c(c1C)c1ccccc1n2Cc1ccccc1
Reaction time: 8 h

Procedure:
550 μl of methyl 2-mercaptoacetate was added to a slurry of 1.45 g of (82) and 1.6 g of K2CO3 in 15 ml of MeOH, and left with stirring overnight. 30 ml of water was added, and the product isolated as a sticky lump. This lump was dissolved in EtOAc, washed with water, dried and evaporated to give an oil, which slowly solidified. Crystallization from MeOH gave (83). Yield 330 mg. M.p. 132°-4° C.
Reaction SMILES: [C:1]1([Si:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:28]([CH3:31])([CH3:30])[CH3:29])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:27])[CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CC(C)=O>[C:32]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:28]([CH3:30])([CH3:31])[CH3:29])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:27])[CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([O:22][CH3:38])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](Oc1cccc(C(O)CCc2ccccc2C(=O)O)c1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1CCC(O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To the product of Example 2, Step 1 (95 g, 0.187 mol) in acetone (1 L) was added K2CO3 (55 g, 0.374 mol) and MeI (128 mL, 1.31 mol). After refluxing for 1.5 h, the reaction mixture was cooled to r.t. EtOAc (1 L) was then added to the reaction mixture and the K2CO3 was removed by filtration. The filtrate was evaporated to dryness to provide 93 g (98%) of the title ester.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:25]([CH3:26])[C:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.6 g (1.69 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride.0.3 hydrate salt of the title compound with ethereal HCl yield 0.68 g (87%) as a white solid; mp=>260° C.; MS (+) ESI m/z=465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Cl:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a solution of 6-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.12 mmol) in concentrated H2SO4 (0.3 mL) at 0° C. was added KNO3 (14 mg, 0.141 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h and then at room temperature for 20 h and it was poured into ice water (2 g). The precipitate was collected by filtration, giving 31 mg of crude title compound. The sample was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate which was collected by filtration and then dried in air at 50° C. for 4 h to give the title compound (29 mg, 80%) as a yellow powder. Crystallization from DMSO/H2O gave pure compound (18 mg) as yellow microcrystals. mp: 342°-5° C., IR (KBr, cm-1): 3394, 3301, 3248, 3209, 1761, 1701, 1628, 1542. 1H NMR (DMSO-d6): δ7.618 (s, 1H), 12.351 (s, 1H), 12.552 (s, 1H). HRMS: calcd for C9H3ClF3N3O4 (M+) m/z: 308.9763, found: 308.9759.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2,2,2-trifluoroethanol (5.0 g, 50.0 mmol) and triethylamine (10.5 ml, 7.6 g, 75.0 mmol) in 25 ml of methylene chloride at -10° is added methanesulfonyl chloride (4.25 ml, 6.3 g, 55.0 mmol) over 20 min., maintaining the temperature at 0° to -10°. After addition is complete, the mixture is stirred at 0°-5° for 30 min. It is then poured into ice water and additional methylene chloride is added. The layers are separated, and the methylene chloride layer is washed with cold 10% HCl, with cold saturated sodium bicarbonate, with cold water until neutral, and with cold brine. The organic layer is dried over calcium sulfate with swirling and is filtered and the solvent is removed to give 2,2,2-trifluoroethyl methanesulfonate.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=C[CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH:43]5[CH2:42][N:47]([CH3:46])[CH2:44]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.71 (m, 7 H) 1.90 (m, 3 H) 2.42 (s, 3 H) 3.32 (s, 3 H) 3.76 (t, J=7.2 Hz, 2 H) 3.94 (s, 3 H) 4.05 (t, J=13.8 Hz, 2 H) 4.38-4.60 (m, 1 H) 4.76 (d, J=7.8 Hz, 1 H) 7.35-7.59 (m, 2 H) 7.99 (s, 1 H) 8.26 (s, 1 H) 8.29 (d, J=8.3 Hz, 1 H) 8.72 (d, J=6.6 Hz, 1 H). Melting point: 157-162° C. [M+H] calc'd for C25H31F2N7O3, 516; found 516.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(O)(C)C>[ClH:16].[ClH:16].[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:13][CH:14]=1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Yield: 189.4 %

Procedure:
A solution of N-(t-butoxycarbonyl) 4-aminoaniline (5.73 g, 27.5 mmol), and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (8.44 g, 25.0 mmol), in isopropanol (100 ml) was heated at reflux for 3.5 hours before the reaction was allowed to cool to ambient temperature. The solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×100 ml). Drying of this material yielded 4-(4-(N-Boc-amino)anilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline dihydrochloride (13.79 g, 95% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.Cl[C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)=[O:29].C(N(CC)CC)C.O>ClCCl>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[O:29])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Temperature: 25 °C

Procedure:
At 0° C., 220 mg (0.55 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 3 ml of dichloromethane, and 273 mg (1.10 mmol) of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate and 116 μl (0.82 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (28% of theory)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:29])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a 25 mL volume two-necked flask, 500 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 2.3 ml of toluene, 345 mg of dimethyl sulfate and 315 mg of potassium carbonate were added and the mixture was stirred at 5° C. for 24 hours. To the reaction mixture, 2 ml of water and 2.3 ml of toluene were added and the resultant was extracted. Further, the aqueous layer was extracted with 2.5 ml of toluene two times. The organic layers were combined, concentrated under reduced pressure and subjected to column chromatography (hexane: ethyl acetate=5:1) to give 411 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[C:26]1([CH3:33])[CH:27]=[C:28]([CH3:32])[CH:29]=[C:30]([CH3:31])[C:25]=1[N:22]1[C:16]2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=[C:14]([O:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])[C:15]=2[CH:24]=[CH:23]1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-phenyl-1-propanol (0.061 ml, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 49.4 mg (82%) of the title compound as an oil.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([N:17]=[N+]=[N-])[CH2:14][NH:13]1)=[O:11].COC([C@@H]1C[C@H](N)CN1[CH2:30][CH:31]1[CH2:36][CH2:35]CC[CH2:32]1)=O>>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]1[CH2:35][CH2:36][C:31]([CH3:2])([CH3:32])[CH3:30])=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Product: COC(=O)[C@@H]1C[C@H](N)CN1CCC(C)(C)C

Procedure:
(2S,4S)-4-Amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C12H25N2O2 [(M+H)+] 229, obsd. 229.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.Cl.[NH2:15][CH:16](C)[C:17](OC)=O>N1C=CC=CC=1>[CH3:17][CH:16]1[NH:15][C:7](=[O:12])[C:6]2[CH:13]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9]1=[O:11]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COC(=O)C(C)N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(=O)NC(C)C(=O)N2
Temperature: -10 °C
Yield: 50.5 %

Procedure:
A mixture of 17.7 parts of 6-methyl-4H-3,1-benzoxazine-2,4(1H)-dione, 15.0 parts of methyl 2-aminopropanoate monohydrochloride and 62.7 parts of pyridine was refluxed for 6 hours under argon. The reaction mixture was cooled at −10° C. for 1 hour. The precipitate was filtered off, rinsed with water, triturated in ethanol and rinsed with ethanol and 1,1′-oxybisethane, yielding 10.32 parts (50.5%) of 3,4-dihydro-3,7-dimethyl-1H-1,4-benzodiazepine-2,5-dione (interm. 43).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4Cl)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31].CN1CCOCC1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4[NH:28][C@H:29]([CH2:30][OH:31])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of 3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-chloro-1 H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (0.78 mg, 5.2 mmol) and N-methyl morpholine (2 mL). The reaction mixture was heated to 80° C. for 12 h, cooled to room temperature and concentrated with high vacuum. The residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (0.90 g, 69%). 1H NMR (400 MHz, CD3OD) δ 7.36 (1H, s), 7.02–7.23 (6H, m), 6.80 (1H, s), 5.98 (1H, d, J=7.5 Hz), 4.10–4.12 (3H, m), 3.67–3.78 (6H, m), 3.06–3.11 (3H, m), 2.90 (1H, dd, J=7.8, 13.6 Hz), 2.54 (3H, s), 2.12 (3H, s). LCMS (M+H)+ m/z 501 (t=1.30 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[Cl:1][C:2]1[CH:9]=[N+:8]([O-:26])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(-c2cncc(Cl)c2C#N)c1
Solvent: ClCCl
Product: COc1cccc(-c2c[n+]([O-])cc(Cl)c2C#N)c1
Yield: 93.9 %

Procedure:
A solution of 3-chloro-5-(3-methoxyphenyl)isonicotinonitrile (1.60 g, 6.54 mmol) and 77% 3-chloroperbenzoic acid (5.86 g, 26.2 mmol) in dichloromethane (60 mL) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane (100 mL), washed with 1 M sodium sulfite (25 mL), 1 N NaOH (2×25 mL), brined (25 mL), dried (MgSO4) and concentrated to give crude 3-chloro-4-cyano-5-(3-methoxyphenyl)pyridine 1-oxide as white solid (1.60 g). The crude material was used in the next step without purification. MS (ES+) m/z: 261 (M+H); LC retention time: 2.933 min (analytical HPLC Method A).