Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][NH:25][CH2:24][CH2:23]2>COC(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][N:25]([C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=3[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(Cl)=N2
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: COC(C)O
Product: COc1cc2c(cc1OC)CN(C1=Nc3cc(OC)c(OC)cc3S(=O)(=O)N1)CC2
Yield: 50.3 %

Procedure:
3-Chloro-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 1a (154 mg, 0.55 mmol) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 2a (wherein R1 and R4 are hydrogen, and R2 and R3 are methoxy)(138 mg, 0.6 mmol) were dissolved in 20 ml of methoxyethanol and heated at reflux for 72 h. The solvent was removed under reduced pressure. The gummy residue was triturated with isopropanol and the resulting crystals filtered. Recrystallization from dichloromethane afforded 120 mg of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 101, [M+H]+=434.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1>CC(O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([S:20]([N:17]4[CH2:18][CH2:19][O:14][CH2:15][CH2:16]4)(=[O:22])=[O:21])=[CH:24][CH:25]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: COc1ccc2cnc(Cl)nc2c1
Solvent: CC(C)O
Product: COc1ccc2cnc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 2-chloro-7-methoxyquinazoline (1 eq) and 4-(Morpholinosulfonyl) Aniline (1 eq) in 2-propanol was heated at 80° C. overnight. Product was precipitated in the reaction mixture. The precipitate was filtered, washed and dried under vacuum to provide 7-methoxy-N-(4-(morpholinosulfonyl)phenyl)quinazolin-2-amine as a yellow solid in 99% yield. ES/MS m/z 401.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH2:26])=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH:26][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:24]
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)c(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.7 mmol), 3,4-dichlorobenzohydrazide (CAS 28036-91-1, 763 mg, 3.7 mmol) and anhydrous THF (100 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C., 1-Hydroxybenzotriazole hydrate (502.8 mg, 3.7 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (1.4 g, 7.4 mmol) and triethylamine (1.03 mL, 7.4 mmol) at −15° C. The reaction mixture was maintained at −15° C. and stirred for 1 h after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 10 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to furnish a light brown solid. 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.10 (d, J=2.1 Hz, 1H), 7.90 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 5.57 (d, J=6.8 Hz, 1H), 4.44-4.36 (m, 1H), 4.16-4.10 (m, 1H), 2.88-2.80 (m, 1H), 2.37 (s, 3H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>>[C:9]([C:10]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH:4]=[C:2]([CH3:3])[CH3:1])[O:12][C:11]=1[CH3:13])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)=CC=C(C)C
Product: CCOC(=O)C1=C(C)OC(C=C(C)C)C1(C)C

Procedure:
2,5-Dimethyl-2,4-hexadiene and ethyl acetoacetate were reacted utilizing the oxidative addition procedure to obtain 4-carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran. Manganese (III) acetate obtained by the reaction potassium permanganate (19.75 grams) and manganese (II) acetate (122.5 grams) in 250 mls acetic acid was employed for the oxidation. The 2,5-dimethyl-2,4-hexadiene (27.5 gram) and ethyl acetoacetate (32.5 grams) were reacted in the presence of 0.5 grams cupric acetate catalyst. 4Carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran was recovered (61% yield) and hydrogenated in ethanol using a supported palladium catalyst (5% Pd on carbon) to obtain 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran. Essentially pure (97+%) 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran (B.P. 136° C. @9.2 mm Hg; nD23° 1.4642) was obtained upon distillation of the crude product. The product had a green vegetable odor. The structure of the product ##STR23## was confirmed by infrared and nuclear magnetic resonance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:35]([C:37]1[NH:38][C:39]2[C:40]([N:47]=1)=[N:41][C:42]([CH3:46])=[CH:43][C:44]=2[CH3:45])[CH3:36].O.[OH-].[Li+]>ClCCl.C(Cl)(Cl)Cl.C(OCC)(=O)C.CO>[C:1]([O:5][C:6](=[O:22])[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:47]2[C:40]3=[N:41][C:42]([CH3:46])=[CH:43][C:44]([CH3:45])=[C:39]3[N:38]=[C:37]2[CH2:35][CH3:36])=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CC(C)(C)OC(=O)N(c1ccccc1)c1ncc(CO)cn1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cnc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
(5-Hydroxymethylpyrimidin-2-yl)phenylcarbamic acid tert-butyl ester (286 mg, 0.949 mmol) obtained in Step 6 was dissolved in dichloromethane (10 mL), and triethylamine (0.265 mL, 1.90 mmol) and methanesulfonyl chloride (0.147 mL, 1.90 mmol) were added to the solution at 0° C., followed by stirring at room temperature for 2 hours. After the reaction was finished, the reaction mixture was added with methanol to decompose excess reagents, and the mixture was diluted with chloroform and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the residue was dissolved in DMF (10 mL), and the solution was added with 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (234 mg, 1.34 mmol) and lithium hydroxide monohydrate (56.0 mg, 1.34 mmol) followed by stirring at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to obtain [5-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)pyrimidin-2-yl]phenylcarbamic acid tert-butyl ester (412 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:17][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][N:10]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(-c3ccc(Br)cc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2c(-c3ccc(Br)cc3)onc12
Yield: 72.4 %

Procedure:
A mixture of 6.4 g (0.0222 mole) of (4-bromophenyl)-7-methyl-2,1-benzisoxazole, 4.0 g (0.0225 mole) of N-bromosuccinimide and 0.1 g of dibenzoyl peroxide in 250 ml of carbon tetrachloride was heated at reflux for 3 hr under flood light illumination and an argon atmosphere, and filtered while still hot. The filtrate was washed twice with 200 ml portions of 10% sodium bicarbonate solution and twice with 200 ml portions of water and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to a solid residue. The solid was recrystallized from 2-propanol to give 5.9 g (73%) of fluffy yellow crystals, m.p. 159°-161° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][C@@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:23])[CH2:21][CH3:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClCCl.CN(C)C=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([NH:23][C:10]([C@H:8]2[CH2:9][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[CH2:21][CH3:22])=[CH:18][CH:19]=1
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Reactant: CC[C@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
To a solution of (1S,2S)-2-phenyl-cyclopropanecarboxylic acid (170 mg, 1.05 mmol) in dichloromethane (10 ml) was added oxallyl dichloride (145 mg, 1.2 mmol) followed by a few drops of N,N-dimethylformamide at RT. The reaction mixture was stirred at RT for 45 mins before it was concentrated down and dissolved in dichloromethane (1.5 ml). The solution was added slowly to a solution of (S)-1-(4-bromo-phenyl)-propylamine (250 mg, 1.0 mmol, HCl salt) and triethylamine (222 mg, 2.2 mmol) in dichloromethane (10 ml) at 0° C. The resulting reaction mixture was stirred at RT for 1.5 h. Water was added and the aqueous layer was extracted by dichloromethane. Organic layer was dried by magnesium sulfate and concentrated. The residue was purified via column chromatography on silica gel to afford (1S,2S)-2-phenyl-cyclopropanecarboxylic acid [(S)-1-(4-bromo-phenyl)-propyl]-amide (330 mg, 92%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (d, J=8.6 Hz, 2H), 7.15-7.23 (m, 2H), 7.11 (d, J=7.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.98 (d, J=7.3 Hz, 2H), 5.75 (d, J=7.6 Hz, 1H), 4.77 (q, J=7.5 Hz, 1H), 2.31-2.41 (m, 1H), 1.65-1.81 (m, 2H), 1.48-1.59 (m, 2H), 1.12-1.23 (m, 1H), 0.82 (t, J=7.4 Hz, 3H); LRMS (ESI) (M+1)=360.04. Molecular Formula=C19H20BrNO.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(NCc3cccc(Cl)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound (2-A) was prepared from 6′-(3-chloro-benzylamino)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-2b). To a solution of (I-2b) in CH2Cl2 was added trifluoroacetic acid. After stirring at room temperature for 3 h, the mixture was poured into 1N NaOH and extracted with CH2Cl2 (1×35 mL). The organic layer was washed with brine, dried and concentrated to afford the title compound as a free amine (2-A).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C([N:19](CC)CC)C.COC(Cl)=O.N>C(#N)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:19])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CCN(CC)CC
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Agent: COC(=O)Cl
Agent: N
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To a suspension of 4-methyl-3,5-dinitrobenzoic acid (3) (1.5 g) in acetonitrile (22.5 g, 30 mL) and triethylamine (0.87 g, 1.2 mL) at −10° C. is slowly added a solution of methylchloroformate (0.723 g, 0.6 m-L) in acetonitrile (2.25 g, 3 mL). The resulting mixture is agitated at −10° C. for about 1 hour, whereupon ammonia gas (excess) is bubbled though the mixture for about 30 minutes. The resultant mixture is allowed to age at about −5 to −10° C. for 12 hours, whereupon the mixture is added to a mixture of ice and water (100 mL). The solid that precipitates is filtered and dried to provide 4-methyl-3,5-dinitrobenzamide (6) (1.36 g, 91% Yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([CH:21]=[CH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C=Cc1ccccc1
Yield: 78.2 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-5-phenylethynyl-phthalazine (0.47 g, 1.12 mmoles), prepared as described in example 62, in THF (50 ml) was hydrogenated in Parr in the presence of 10% Pd/C (0.1 g) for 2 hours, then filtered, brought to dryness and flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The fractions containing the product were concentrated and taken up in 20 ml of ethyl ether/petrolatum 1:1. The crystallised was filtered and dried under vacuum at 40° C. to give 0.37 g of the title compound (yield: 78%). m.p.: 180-182° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:26])[N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][N:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[O:26])[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]=3[NH:29][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(-c3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
850 mg (2.5 millimoles) of Compound 101 was suspended in 5 ml of glacial acetic acid, and 0.26 ml (5.5 millimoles) of hydrazine monohydrate was added to the suspension. The mixture was heated under reflux for 5 hours and the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, and recrystallized from DMF-water to obtain 440 mg (yield 52.4%) of Compound 1.
Reaction SMILES: [Br:1][CH:2]([CH2:15]Br)[CH2:3][CH:4]([OH:14])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Ca+2].[OH-].[Br-].[Ca+2].[Br-]>CO.O>[Br:1][C@H:2]1[CH2:15][O:14][C@@H:4]([CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: OC(COCc1ccccc1)CC(Br)CBr
Agent: [Br-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Br[C@H]1CO[C@@H](COCc2ccccc2)C1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A solution of 10.0 g of product from Example 3 in 25 ml of methyl alcohol is diluted with 50 ml of distilled water. To this heterogeneous mixture isadded 1.6 g of calcium hydroxide followed by 16.95 g of calcium bromide. The reaction is stirred vigorously while heating in an oil bath, at 100° C., for 24 hours. The internal temperature is maintained at 85° C. The reaction is cooled, extracted with methylene chloride, filtered thru diatomaceous earth and the layers partitioned. The organic layer is washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 7.18 g of an oil. The oil is purified by chromatography (Silica Gel: 5% ethyl acetate/hexane) to give 2.82 g of thetrans-isomer and 2.89 g of the cis-isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:37]=[CH:36]3)[C:10]=1[CH2:49][CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:54][B:55](OC(C)C)[O:56]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:37]([B:55]([OH:56])[OH:54])=[CH:36]3)[C:10]=1[CH2:49][CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of tert-butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-ethylpyridin-2-yl)-1H-indole-1-carboxylate, prepared according to the protocol described in Example 412, step 3 (3.07 g, 4.59 mmol), triisopropylborate (1.17 mL, 5.51 mmol) in THF (15 mL), at −78° C. was added while stirring, LDA (3.67 mL, 1.5 M in cyclohexane, 5.51 mmol). The mixture was stirred for 0.5 h after the addition and the cooling bath was removed to allow the reaction mixture to warm to room temperature and stirred for an additional 0.5 h. The reaction was quenched with 6 N HCl at 0° C. and acidified to pH 4 and the mixture was diluted with DCM and water. The organic layer was separated, washed with water, brine and dried over anhydrous Na2SO4. The filtrate was concentrated and chromatographed (ethyl acetate in DCM, 0-40%) to give the boronic acid intermediate as light yellow powder (0.78 g) in 24% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16]O)[C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CS(Cl)(=O)=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([C:11](=[CH2:16])[C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO)C(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)C(=O)OCc1ccccc1
Temperature: 20 °C
Yield: 92 %

Procedure:
To a flame dried three neck round bottom flask, was added methyl 2-(benzyloxycarbonyl)-3-hydroxypropanoate (129 g, 509 mmol), anhydrous methylene chloride (2 L), and methanesulfonyl chloride (49.3 mL, 636 mmol). The mixture was cooled to −15° C.→20° C. for 20 min while stirring with a mechanical stirrer. Triethylamine (213 mL, 1527 mmol) was added dropwise ensuring the inner temperature of the reaction mixture did not exceed 0° C. (the addition of the first equivalent of triethylamine was exothermic). After the addition of triethylamine, the mixture was stirred at 0° C. for 30 min, then the cooling bath was removed and the mixture was stirred at room temperature for 1.5 h. Methanol (21 mL) was added to quench excess methanesulfonyl chloride. The mixture was washed portionwise with 0.5% aq. potassium hydrogen sulfate to pH 5, then sat. sodium bicarbonate/brine (1:2 by volume) and brine. The methylene chloride solution was dried over anhydrous sodium sulfate. After filtration, the solvents were removed and the residue was subjected to column chromatography on silica gel using 1:9 ethyl acetate/hexanes as eluent to afford the title compound as a colorless very viscous oil, which recrystalized upon standing at room temperature, 0° C. and −15° C. (111 g, 92% yield). 1H-NMR (DMSO-d6) δ 8.96 (s, 1H), 7.39-7.35 (m, 5H), 5.76 (s, 1H), 5.60 (s, 1H), 5.10 (s, 2H), 3.71 (s, 3H); 13C-NMR (DMSO-d6) δ 163.7, 153.5, 136.3, 133.3, 128.8, 128.3, 128.1, 127.8, 65.9, 52.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCCc4cc(C)ccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 94% yield from 6-methyl-1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 147°-148° C.; LC-MS: 336 (MH+); anal. RP18-HPLC RT: 4.51 min.).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:6]2.[NH2:16][C:17]1[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][C:20]([CH2:21][C@@H:22]([CH2:26][C:27](=[O:46])[N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:30][CH2:29]2)[C:23](O)=[O:24])=[CH:19][C:18]=1[Cl:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:16][C:17]1[C:48]([C:49]([F:51])([F:50])[F:52])=[CH:47][C:20]([CH2:21][C@@H:22]([CH2:26][C:27]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:30][CH2:29]2)=[O:46])[C:23]([N:13]2[CH2:14][CH2:15][N:10]([CH:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)[CH2:11][CH2:12]2)=[O:24])=[CH:19][C:18]=1[Cl:53]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CN1C2CCC1CC(N1CCNCC1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1CC(N1CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
850 mg (2.4 mmol) 8-methyl-3-piperazin-1-yl-8-aza-bicyclo[3.2.1]octan were added to a solution of 1.04 g (1.88 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid, 642 mg (2.0 mmol) TBTU and 1.64 mL (9.6 mmol) ethyldiisopropylamine in 20 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was combined with 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance was suction filtered, washed with 50 mL water and dried in the air and purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:85:5).