Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2-methyl-hexan-3-ol (42 mg, 3.0 eq, 0.32 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.3 mg (15%). 50% de 4R,3S: 50% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.93-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.95 Hz, —CH(CH3)2), 1.65-1.89 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.22-3.32 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.82-3.97 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.54-4.70 (m, 1H, —CH(CH3)2), 4.78-4.88 (m, 2H, —HNCH2-Pyr), 5.03-5.14 & 6.08-6.20 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.22-7.36 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.49-7.58 (m, 1H, Pyr-H), 7.71 (d, 1H, J=7.90 Hz, Pyr-H), 8.47-8.73 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (50). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]([O:9]C)=O)[S:5][C:4]2[C:11]3[C:16]([CH2:17][CH2:18][C:3]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Cl:19][CH2:20][C:21]#[N:22]>Cl.O1CCOCC1>[Cl:19][CH2:20][C:21]1[NH:22][C:7](=[O:9])[CH:6]2[CH:2]([C:3]3[CH2:18][CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]=3[S:5]2)[N:1]=1
Reactant: N#CCCl
Reactant: COC(=O)C1SC2=C(CCc3ccccc32)C1N
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NC(CCl)=NC2C3=C(SC12)c1ccccc1CC3
Temperature: 100 °C

Procedure:
A solution of EXAMPLE 12D (200 mg) and 2-chloroacetonitrile in 4M hydrochloric acid in dioxane (4 mL) was heated at 65° C. for 18 hours. The mixture was cooled, filtered and the solid heated in N,N-dimethylformamide (6 mL) at 100° C. for 2 hours. The solution was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 145 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 12.85 (bs, 1H), 7.55 (m, 1H), 7.31-7.38 (m, 3H), 4.60 (s, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.93-2.96 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([CH2:18][C:19]([OH:21])=O)([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([C:15](=[O:17])[N:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:19](=[O:21])[CH2:18]2)[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC1(C(=O)O)CCN(Cc2ccccc2)CC1
Reactant: NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of (1-benzyl-4-carboxypiperidin-4-yl)acetic acid.hydrochloride (31.3 g) in dimethylformamide (200 ml) was added dicyclohexylcarbodiimide (20.6 g). The mixture was stirred for one hour at room temperature, to which were added benzyloxyamine hydrochloride (16 g) and triethylamine (14 ml). The mixture was stirred for further one hour at room temperature, followed by evaporating off the solvent under reduced pressure. To the residue were added acetic anhydride (150 ml) and sodium acetic anhydride (21 g). The mixture was stirred for one hour at 100° C., then insolubles were filtered off, and the solvent was evaporated off under reduced pressure. To the residue was added ethyl acetate (200 ml), to which was further added a saturated aqueous solution of sodium hydrogencarbonate until the aqueous layer became alkaline. The organic layer was washed with water, dried over anhydrous magnesium sulfate, followed by evaporating off the solvent under reduced pressure. To the residual oil was added 100 ml of acetonitrile, and insolubles were filtered off. Acetonitrile was evaporated off, and the residue was recrystallized from acetonitrile-ethyl ether to obtain 16.5 g of a colorless solid, m.p. 146° to 152° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:14][C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:6]([O:5][C:4]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:2]([CH3:1])[CH:3]=2)=[CH:7][C:8]=1[CH3:16])=[O:15]
Reactant: CC(=O)c1c(C)cc(Oc2cc(C)cc(C)c2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(C)cc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (6.30 g, 23.5 mmol) in acetonitrile (47.0 mL) was added tetrabutylammoniumtribromide (TBABr3, 11.9 g, 24.7 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (8.3 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][CH2:9][CH2:10][NH:11][C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:8].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][NH:11][C@@H:12]2[CH2:14][C@H:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][CH2:3]1
Reactant: ClCCN[C@@H]1C[C@H]1c1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Product: Cl
Temperature: 80 °C
Yield: 56 %

Procedure:
N-methyl piperazine, 0.68 mL (6.13 mmol), was added over a solution of the N-(2-chloroethyl)-N-[(trans)-2-phenylcyclopropyl]amine (Intermediate B) 0.6 g (3.06 mmol) in 60 mL DMF, followed by the addition of K2CO3 (3.06 mmol). The mixture was stirred at 80° C. and the progression was monitored by TLC, after completion, the solvent was evaporated to dryness. DCM and a K2CO3 solution were added to the crude. The organic layer was extracted, washed with water, brine and dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (DCM-MeOH from 100:0 to 80:20). HCl (2M in diethyl ether), 3 mL, was added dropwise to a solution of the N-[(trans)-2-phenylcyclopropyl]ethane-1,2-diamine derivative in diethyl ether (10 mL) until solid precipitation. The mixture was stirred for 2 hours, the solid was filtered, washed with diethyl ether and dried under reduced pressure to give 0.58 g of N-[2-(4-methylpiperazin-1-yl)ethyl]-N-[(trans)-2-phenylcyclopropyl]amine hydrochloride salt. Yield: 56%. 1HNMR (DMSO-d6) δ (ppm): 1.24 (q, 1H), 1.63 (quin, 1H), 2.62 (m, 1H), 2.78 (s, 3H), 3.00 (m, 1H), 3.28 (br, 4H), 3.73 (br, 2H), 3.44 (br, 2H), 3.61 (br, 4H), 7.17 (t, 2H), 7.20 (d, 1H), 7.28 (t, 2H), 10.12 (br, 1H), 11.90 (br, 1H). MS (M+H): 260.09
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccccc2)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (49.2 mg) with purity >90%. MS (pos) m/z 399.1,401.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1([C@@H]([NH:20][C@H:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][C@H:22]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:20][C@H:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][C@H:22]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N[C@@H](C)c1ccccc1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Temperature: 40 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
To a hydrogenator were charged ethyl (7R,8S)-8-((S)-1-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1A (1417 g, 2.8 moles, c.f: WO2004098516, prepared analogous to U.S. Pat. No. 6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40° C. until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ˜2 L until most ethanol was removed (<0.5%) and residual moisture content was <1,000 ppm. Batch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate. The mixture was heated to 80° C. until clear, then cooled 65°-70° C. Seed crystals of 1 (5 g) were added and the batch was cooled to 50° C. over 2 hours, then further cooled to 20° C. over 4 hours and held for ˜10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vaccum at ˜35° C. until volatiles were reduced below ˜1% (LOD). Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300 MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H,), 3.20-3.13 (m, 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm×150 mm i.d., 3.5 μm particle size, 0.05% NH4OH (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-2].[Ca+2]>CN1CCCC1=O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Brc1ccccc1
Agent: [Ca+2]
Agent: [Na+]
Agent: [O-2]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.14 g (20 mmol) of bromobenzene, 11.2 g (200 mmol) of calcium oxide, 60 ml of N-methyl-2-pyrrolidone and each catalyst compound and each organophosphorus compound ligand indicated in Table 2 were placed in 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours, respectively. After the completion of the reaction, the amount of 4-methylbiphenyl formed was analyzed by means of high performance liquid chromatography. The results are shown in Table 2.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5](=[CH2:7])[CH2:6][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)CC(CF)N1C(=O)c2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)CC(CF)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1-fluoro-2-phthalimido-4-methyl-4-pentene (28.3 g, 115 mmoles) prepared as in step B above, N-bromosuccinimide (20.4 g, 115 mmoles), carbontetrachloride (300 mL), and a few mgs of benzoyl peroxide is heated under strong reflux (325 W lamp) during 7.5 hours. After cooling and filtration, the solution is washed with water (100 mL, 3 times), dried over magnesium sulfate and concentrated. The oily residue (quantitative), consisting mainly of the title compound plus some 1-fluoro-2-phthalimido-4-methyl-5-bromo-3-pentene, is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=[O:5].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:18][CH:19]2[CH2:20][CH2:21]2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)=[O:5]
Reactant: O=C(NCC1(CC2CC2)CCC2(CC1)OCCO2)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1

Procedure:
2,4-Dichloro-N-[(8-cyclopropylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)methyl]benzamide (11 g; 27.6158 mmol) was dissolved in THF (80 ml) and HCl (2M; 80 ml) and the solution stirred at ambient temperature for 18 hours. The solution was adjusted to pH 9 with 10N NaOH solution and extracted with DCM (2×75 ml). The combined organics were dried (MgSO4) filtered and evaporated to give an oil which was crystallised from EtOAc isohexane as a white solid (8.0 g) 1H NMR δ (ppm) (CDCl3): 7.67 (1 H, d, J=8.3 Hz), 7.44 (1 H, d, J=2.0 Hz), 7.34 (1 H, dd, J=2.0, 8.3 Hz), 6.37 (1 H, s), 3.72 (2 H, d, J=6.4 Hz), 2.57-2.49 (2 H, m), 2.39-2.31 (2 H, m), 1.92-1.80 (4 H, m), 1.43 (2 H, s), 0.77-0.69 (1 H, m), 0.58-0.54 (2 H, m), 0.11 (2 H, q, J=5.0 Hz). MS (m/e)=354.
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@H:6]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[OH-:29].[Na+].OO>O1CCCC1.O>[C:18]([O:17][C:15]([NH:14][C@@H:6]([CH2:5][C@H:4]([CH2:1][CH2:2][CH2:3][OH:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15.58 g (39 mmol) of di-tert-butyl (2S,4S)-4-allyl-2-tert-butoxycarbonylamino-pentanedioate 5a were dissolved in 200 mL of tetrahydrofuran (THF) and cooled in an ice-bath. Over a period of about 20 minutes, 54.6 mL (54.6 mmol) of 1 M diboran/tetrahydrofuran complex in tetrahydrofuran were added dropwise with ice-cooling and under nitrogen, and the mixture was stirred on ice for 2 h and at room temperature overnight. It was cooled again to 0° C. and 58.5 mL of 1 N aqueous sodium hydroxide solution and 58.5 mL of 30% aqueous hydrogen peroxide solution were then added dropwise. After 60 minutes, the mixture was diluted with water, the tetrahydrofuran was distilled off and the remaining aqueous solution was extracted with ethyl acetate. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.[C:10]([O:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16](Cl)=[O:17])(=[O:12])[CH3:11]>[Na+].[OH-].ClCCl>[C:10]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:1])=[O:17])(=[O:12])[CH3:11]
Reactant: OCc1cccc(O)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
3-hydroxymethylphenol (25.25 g, 0.2 moles) is dissolved in a 5% hydroxide sodium solution (160 ml). To the so obtained solution an acetylsalicylic acid chloride solution (40.4 g, 0.2 moles) in dichloromethane (50 ml) is added at roam temperature, under stirring. The mixture is maintained at room temperature under stirring for 2 hours and then extracted with dichloromethane (2×100 ml). The organic phase is separated, anhydrified with sodium sulphate and the solvent evaporated under vacuum. The residue is crystallized from a mixture of ethyl acetate and hexane. 3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:18])([CH2:16]O)[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[C:11]([CH3:18])([CH3:16])[CH2:10][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: Nc1ncc(Br)cc1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1cc(Br)cnc1N
Temperature: 0 °C
Yield: 38.7 %

Procedure:
To a suspension of 2-amino-5-bromopyridin-3-ol (1.42 g, 7.51 mmol) in THF (40 mL) was added methyl 2,2-dimethyl-3-hydroxypropionate (1.2 mL, 9.0 mmol) and triphenyl phosphine (2.36 g, 9.00 mmol). The mixture was cooled to 0° C., then treated with diethyl diazodicarboxylate (1.70 g, 9.75 mmol). The mixture was heated in microwave at 120° C. for 20 min. The solvent was concentrated, and the residue was purified by chromatography (silica gel, hexanes/EtOAc, 75:25 to 60:40) to give the title compound (0.88 g, 39%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.1 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 4.65 (br s, 2H), 3.96 (s, 2H), 3.71 (s, 3H), 1.34 (s, 6H); ESI MS m/e 303 (M+H)+.
Reaction SMILES: CCN=C=N[CH2:6][CH2:7][CH2:8][N:9]([CH3:11])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:23]2[CH:24]=[CH:25]C=[CH:27][C:22]=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:9]1[C:8]2[C:23](=[CH:22][CH:27]=[CH:6][CH:7]=2)[CH2:24][CH:25]=[CH:11]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C1=CNc2ccccc2C1

Procedure:
In Step A, a substituted benzaldehyde is condensed with a substituted acetophenone or 1-pyridin-3-yl-ethanone (V), in the presence of an inorganic base such as NaOH, in a polar protic solvent such as MeOH, to give the corresponding α,β-unsaturated ketone of formula (VI). This product can be reduced to the corresponding saturated ketone by hydrogenation in presence of a catalyst, such as platinum (IV) oxide, in a mixture of polar solvents, such as ethanol and EtOAc, as described in Step B. When R1 or R2 are chloro, this moiety can simultaneously be reduced using palladium on carbon as a catalyst instead of platinum (IV) oxide. In step C, the aniline (VII) can be acylated by heating at reflux in the presence of an acyl chloride such as methyl oxalyl chloride in an apolar solvent such as toluene. The amide (VIII) can cyclize by heating at reflux in a polar protic solvent, such as methanol, in the presence of an inorganic base, such as potassium carbonate, as described in Step D to afford the corresponding 1,4-dihydroquinoline. When R1 is a carboxylic ester moiety in the coupling Step A, both the ester and corresponding carboxylic acid can be formed by hydrolysis; the acid can then be coupled with an amine NHR9R10 in the presence of coupling agents such as EDCI and BOP and an organic base such as diisopropylethylamine in a polar solvent such as tetrahydrofuran. The amide of generic formula (IX) can undergo the same Steps described above from B to D to give the corresponding 1,4-dihydroquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:4](=[O:6])[C:3]3[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=3)[NH:1][C:31]2=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(=O)[nH]c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.50 g, 7.2 mmol) in triethylamine (2.50 mL, 18.0 mmol) and 1,4-dioxane (20 mL) was added 1-chloro-4-isocyanatobenzene (1.4 g, 9.3 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The mixture was then cooled to rt and the solid was filtered, then rinsed with ether (2×) to afford methyl 3-(4-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1.56 g, 66%). LC-MS: (FA) ES+ 331; 1H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.74 (dd, J=8.2, 1.4 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:27].C(O)C.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[O:15])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:27]
Reactant: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)N(C)C(=O)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)CCCc2ccc(NC(=O)c3ccc(C(=O)O)cc3)cc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
850 mg of ethyl p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-8-yl)carbamoyl]benzoate were dissolved in 20 ml of tetrahydrofuran and 10 ml of ethanol and treated with 10 ml of 1.2N NaOH yielding a two-phase mixture. The mixture was stirred intensively at 35° C. for 8 hours, poured into an ice/conc. HCl solution and extracted thoroughly with ethyl acetate. The resulting product was washed with a small amount of NaCl solution, dryed, and concentrated, and the remaining residue was repeatedly boiled in ethyl acetate and dryed yielding 400 mg of p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-8-yl)carbamoyl]benzoic acid as beige crystals, m.p. >270° C.