Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C@H:50]([NH:60]C(OC(C)(C)C)=O)[C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])=[CH:45][CH:44]=1)=[O:41])[C:9]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([NH2:15])=[O:14])=[O:10])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:83]([N:90]1[C:94](=[O:95])[CH:93]=[CH:92][C:91]1=[O:96])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>ClC(Cl)C.O>[NH2:7][C@H:8]([C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH:92]1[CH2:93][C:94](=[O:95])[N:90]([CH2:83][C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:91]1=[O:96])[C:13]([NH2:15])=[O:14])=[O:10])[CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C@@H:50]([C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])[NH2:60])=[CH:45][CH:44]=1)=[O:41]
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)Nc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: O
Product: NC(=O)[C@H](CSC1CC(=O)N(Cc2ccccc2)C1=O)NC(=O)[C@@H](N)CCNC(=O)Oc1ccc(C[C@H](N)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
238 mg (0.25 mmol) of the compound of example 1B was dissolved in 10 ml dichloroethane. 0.12 ml Triethylsilane, approx. 10 ml trifluoroacetic acid and approx. 0.5 ml water was added. The reaction mixture was stirred for approx. 30 min at room temperature. 100 ml dichloroethane were added and the reaction mixture was evaporated under reduced pressure to approx. 1 ml of solvent volume. Approx. 100 ml water was added and the reaction mixture was extracted three times with approx. 50 ml dichloromethane. To the aqueous phase 15 ml of acetic acid was added. The aqueous phase was frozen and lyophilized. The lyophylistae was dissolved in approx. 50 ml methanol and 0.183 mg (0.98 mmol) N-benzylmaleimide was added. The reaction mixture was stirred over night at room temperature. The reaction mixture was evaporated to dryness and redissolved in approx. 5 ml methanol and purified by preparative RP-HPLC on a C18 with a water/methanol gradient. The fractions were collected in test tubes of 20 ml on an automated fraction collector. To ensure sufficient acidity each vial was filled with 0.5 ml acedic acid prior to collection. All fractions containing the compound of example 1C were combined. Acetonitrile was partially removed on a rotary evaporator at 30° C. water bath temperature and approx. 50 mbar for approx. 30 min. After addition of 0.5 ml acedic acid, the remaining solution was lyophilized. The total yield was 168 mg (0.24 mmol, 98% of theory) of the desired product.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH2:13]([OH:19])[CH2:14][O:15][CH2:16][CH2:17][OH:18]>ClCCl>[Cl:12][CH2:11][O:10][C:8]([O:19][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:8]([O:10][CH2:11][Cl:12])=[O:9])=[O:9]
Reactant: O=C(Cl)OCCl
Reactant: OCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)OCCOCCOC(=O)OCCl
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol (0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with good stirring under a dry N2 atmosphere. After 10 min. at 7° C. and 6 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure (10 mm Hg) to give 1.26 g (86%) title product. 1H NMR (300 MHz, CDCl3): δ 3.72 (m, 2×CH2 --O), 4.34 (m, 2×CH2 --O--C=O), 5.71 (s, 2×Cl--CH2 --O). 13C NMR (75 MHz, CDCl3): δ 67.6 (2×CH2 --O), 68.5 (2×CH2 --O--C=O), 72.1 (2×Cl--CH2 --O), 153.2 (2×C=O).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and (4-chloro-phenyl)-piperidin-4-yl-methanone via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C24H26ClNO6 [M+H]+: 460.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCOC(C)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of compound 37 (0.600 g, 2.34 mmol) in DCM (20.00 mL) was added tert-butyl 1-piperazinecarboxylate (0.566 g, 3.04 mmol) and TEA (0.422 mL, 3.04 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.53). The reaction mixture was complete after stirring at room temperature for 1 hr, as indicated by the absence of the starting material (TLC). Water was added and aqueous layer was extracted twice with DCM. Combined extracts were sequentially washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to afford a yellow solid. The solid was triturated with DCM and hexanes, and then filtered to yield compound 38 as a yellow solid (0.789 g, 100% HPLC purity, 83% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.60 (d, J=3 Hz, 1H), 8.47 (dd, J1=3 Hz, J2=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 3.37 (m, 4H), 3.23 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])=O.[Na+].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(Cl)c1C(=O)OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2nc1C(=O)OC
Yield: 134.8 %

Procedure:
A stirred mixture of dimethyl 4,7-dichloroquinoline-2,3-dicarboxylate (5.00 g, 15.9 mM), sodium formate (1.63 g, 23.9 mM) and tetrakis(triphenylphosphine)palladium(O) (0.92 g, 0.80 mM) in anhydrous dimethylformamide (75 mL) under a nitrogen atmosphere was heated at 90°-95° C. for 7 hr. No reaction occurred so the reaction mixture was degassed and an additional quantity of tetrakis(triphenylphosphine)palladium(O) (0.92 g, 0.80 mM) was added and the reaction mixture again heated at 90°-95° C. for 6 hr. The cooled reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave an gummy solid (6.0 g). Trituration of this residue with ethyl acetate and subsequent filtration separated a crystalline solid which was shown to be dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate. The filtrate was concentrated and the residue was flash chromatographed over silica gel (eluant: hexane/ethyl acetate, 3/2) to provide the title diester (1.13 g, 25.4%) as a light yellow crystalline solid; MS(CI): 280 (M+H). 300-MHz 1H NMR (DMSO d6), 9.15 (s, 1H), 8.33 (d, 1H, J=9 Hz), 8.25 (d, 1H, J=2 Hz), 7.86 (dd, 1H, J=9 Hz, 2 Hz), 3.93 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCC(Nc1nccc(-c2cnc3c(NC4CCC(N)CC4)nccn23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (110 mg, 0.17 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N-{3-[2-(3-amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 27 mg, 16.4%). 1H NMR (300 MHz, CD3OD): δ 8.67 (s, 2H), 8.43 (brs, 1H), 7.57-7.55(m, 3H), 7.44-7.31(m, 4H), 5.38 (s, 1H), 4.08 (brs, 1H), 3.21-3.16(m, 3H), 2.42-2.25(m, 6H), 1.75-1.73(m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 19.1 g. of N-benzylpiperazine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-benzyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 275°-286° (dec.).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:35][CH2:36][OH:37]>O1CCOCC1.CCOC(C)=O>[OH:37][CH2:36][CH2:35][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)N(CCO)CCC2)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
N-(1,2,3,4-Tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (100 mg, 0.304 mmol), potassium carbonate (126 mg, 0.913 mmol), sodium iodide (9 mg, 0.06 mmol) and 2-bromoethanol (216 ul, 3.04 mmol) in dioxane (1 ml) were heated at 60° C. for 8 d. After cooling to ambient temperature the reaction mixture was diluted with EtOAc (10 ml), filtered and concentrated in vacuo to give the crude product which was purified on a silica SPE column. Elution with an EtOAc/60-80° C. petroleum ether gradient gave the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, 2H), 7.78 (s, 1H), 7.70 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.19 (d, 1H), 6.93 (d, 1H), 6.74 (dd, 1H), 3.87 (m, 2H), 3.49 (t, 2H), 3.35 (m, 2H), 2.75 (t, 2H), 1.97 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:9][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 1-Pyridin-2-yl-ethylamine and 1-Boc-4-piperidone with NaBH(OAc)3 in CH2Cl2 gave 4-(1-Pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:39][C:37]2[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ncccc23)CC1
Reactant: Cc1ccc(F)cc1O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cccnc2n1-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 6 (50.0 mg, 113 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6, and purification by preparative HPLC. Yield: 28 mg.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]3)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:19][OH:20]>>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][C:10](=[N:19][OH:20])[CH2:9][CH2:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: NO
Reactant: O=C1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: Cl
Product: ON=C1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-(3,4-Methylenedioxy)benzyl-4-piperidone oxime is prepared from 1-(3,4-methylenedioxy)benzyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:15]([O:17]C)=[O:16])=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8][CH:7]=2)=[O:2].[Li+].[OH-]>C1COCC1.O>[CH:13]([C:10]1[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=1)=[CH:5][C:4]1[C:15](=[O:17])[O:16][CH:1]([OH:2])[C:3]=1[CH:12]=2)=[O:14]
Reactant: COC(=O)c1cc2cccc(C=O)c2cc1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc2cc3c(cc12)C(O)OC3=O
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of the impure methyl 3,5-diformyl-2-naphthoate in THF (10 mL) at rt was added 1.0 M aqueous LiOH (5 mL, 5 mmol). After 1.5 hours, the reaction mixture was diluted with H2O and washed with Et2O. The aqueous layer was acidified with 1.0 M aqueous HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (200 mg, 19% from methyl 3,5-diethenyl-2-naphthoate) as a white solid.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:6][CH:5]=1.[H-].[CH2:20]([Al+]CC(C)C)C(C)C>C1COCC1>[O:17]1[CH2:16][CH2:15][CH2:20][O:14][CH:13]1[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:18])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCCC2OCCO2)cc1
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(CCCC2OCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution of 2.85 g (11.4 mmol) of ester 169 in 25 mL of THF at 0° C. was added 4.4 mL (24.7 mmol) of diisobutylaluminum hydride and the resulting mixture was allowed to stir at 0° C. for 15 min. The reaction was quenched with saturated potassium sodium tartrate and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated to yield 2.58 g of the crude alcohol 170 as an oil. 1H NMR consistent with the product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[C:4](=[O:25])[CH2:3]1.O[C@H]1CNC(=O)C1>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[C:4](=[O:25])[CH2:3]1
Reactant: COc1ccc(CN2C[C@@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Agent: O=C1C[C@@H](O)CN1
Product: COc1ccc(CN2C[C@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
P-506 was prepared in a similar manner as that described above for P-248 except starting with (R)-4-Hydroxy-pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) 8.40 (t, J=1.9 Hz, 1H), 8.17 (dd, J=1.7, 8.2 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.22 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.61-4.48 (m, 2H), 4.41 (d, J=14.8 Hz, 1H), 3.85-3.81 (m, 3H), 3.56 (dd, J=5.6, 10.9 Hz, 1H), 3.24 (dd, J=1.8, 10.8 Hz, 1H), 2.75 (dd, J=6.5, 17.3 Hz, 1H), 2.44 (dd, J=2.1, 17.4 Hz, 1H), 2.12 (br s, 1H) ppm. LC/MS=95.6%, 343.1 (APCI+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][CH2:7][CH2:8][OH:9])[CH:4]=[CH2:5].[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:3]([O:6][CH2:7][CH2:8][O:9][CH2:12][CH:11]=[CH2:10])[CH:4]=[CH2:5]
Reactant: C=CCOCCO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOCCOCC=C
Yield: 82.9 %

Procedure:
Sodium hydride (NaH, 5.0 g, 0.208 mol) was slowly added to a solution of 2-allyloxy-ethanol (20 mL, 0.187 mol) while stirring. Allyl bromide (32 mL, 0.370 mol) was added and the mixture was stirred at 60° C. for 10 hours. After cooling, the reaction mixture was filtered and a dark oil was obtained after solvent evaporation. The oil was fractionally distilled to give 22 grams of 3-(2-allyloxy-ethoxy)-propene (0.155 mol, yield 83%) as a colorless oil. 1H NMR (400 Mz, CDCl3): δ 3.6 (t, 2H), 4.0 (d, 2H), 5.1 (d 1H), 5.3 (d 1H), 5.9 (q, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of 1-bromo-4-cyclopropylbenzene [synthesized in analogy to a procedure described in J. Org. Chem. 41:2262-2266 (1976)] (1.58 g, 8.04 mmol) in THF at −78° C. was added n-BuLi (5.08 ml, 1.6M solution in hexane, 8.11 mmol) and the reaction mixture was stirred at −78° C. for 10 min. DMF (1.25 ml, 16.08 mmol) was then added and the reaction mixture was stirred at −78° C. for 15 min. The reaction mixture was then warmed to 0° C. slowly (over 2 h) and stirred at 0° C. for 1 h. The reaction was quenched with sat. NH4Cl (aq) solution and the aqueous phase was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 diethylether:pentane) to give 4-cyclopropyl benzaldehyde (1.10 g, 94%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 1.97 (m, 1H), 1.13-1.06 (m, 2H), 0.84-0.78 (m, 2H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].C([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42]N)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH:8][CH2:42][C@@H:38]1[CH2:39][CH2:40][CH2:41][NH:37]1)=[O:7]
Reactant: NC[C@@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)c(OC)c(C(N)=O)c1OC
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Br)c(OC)c(C(=O)NC[C@@H]2CCCN2)c1OC
Yield: 79.2 %

Procedure:
3-Bromo-2,5,6-trimethoxybenzamide chloride (1.48 g, 4.8 mmol) was reacted with (S)-(-)-1-trityl-2-aminomethylpyrrolidine (1.51 g, 4.4 mmol) in 10 ml dichloromethane at room temperature for 1 h. The solvent was evaporated and the residue was treated with 10 ml ethanol and 0.1 ml conc. HCl during 1 h. After evaporation the residue was partitioned between 0.5M HCl and Et2O. The aqueous phase was made alkaline, extracted with dichloromethane, dried (Na2SO4) and evaporated to give 1.30 g (79%) (S)-(+)-3-bromo-N-(2-pyrrolidinylmethyl)-2,5,6-trimethoxybenzamide. An analytical sample of the hydrochloride was prepared. M.p. 181°-182° C. (EtOH/acetone/Et2O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[N:10]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)nn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
6-(Methoxycarbonyl)-3-methyl-1H-indazole (0.40 g, 2.1 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was ice-cooled. Sodium hydride (85 mg, 60% suspension in oil, 2.1 mmol as NaH) was added and the mixture was stirred at 0° C. for 30 min. 2,4-Dichlorobenzyl chloride (0.45 g, 2.3 mmol) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was extracted with ethyl acetate/water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystalline residue was separated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to give the objective compound (0.54 g, 74%) as colorless crystals.