Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:24])[CH:16]2[C:7]([CH3:22])([C:8]3[C:9](=[O:21])[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:12](=[O:17])[C:13]=3[CH2:14][CH2:15]2)[CH2:6][CH2:5][C:4]1=[O:23].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][C:3]1([CH3:24])[CH:16]2[C:7]([CH3:22])([C:8]3[C:9](=[O:21])[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:12](=[O:17])[C:13]=3[CH2:14][CH2:15]2)[CH2:6][CH2:5][C:4]1=[O:23])(=[O:27])[CH3:26]
Reactant: CC(C)C1=CC(=O)C2=C(CCC3C(C)(CO)C(=O)CCC23C)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1(C)C(=O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture consisting of 60 mg of the 5,6,8,8a,9,10-hexahydro-8-hydroxymethyl-4b,8-dimethyl-2-(1-methylethyl)-1,4,7(4bH)-phenanthrenetrione obtained in Example 2, 0.1 ml of acetic anhydride and 1 ml of pyridine was stirred at room temperature for 2.5 hours. The reaction mixture was poured into ice water, and extracted with ether. The organic layer was washed with an aqueous saturated with sodium chloride, dried with anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by a silica gel column chromatography (eluant: ether/n-hexane=1/2) to obtain 41 mg of 8-(acetoxymethyl)-5,6,8,8a,9,10-hexahydro-4b,8-dimethyl-2-(1-methylethyl)-1,4,7(4bH)-phenanthrenetrione.
Reaction SMILES: [N:1]1([C:65](OC(C)(C)C)=O)[CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:61])[C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH:1]1[CH2:65][CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:61])[C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-MePheOH (0.800 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 0.721 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 in 31% yield. De-t-butoxycarbonylation of BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 (0.400 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-MePhe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 23% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:24])=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24][Br:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1CBr
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixture of 4-methyl-2-(4-phenoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.40 g, 4.14 mmole), N-bromosuccinimide (760 mg, 4.27 mole) and benzoyl peroxide (50 mg, 0.21 mmole) in carbon tetrachloride (18 ml) was refluxed for 8 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (1.69 g). MS: (+) m/z 417.87, 419.87 (M+1, 79Br/81Br).
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Na+].[CH3:21]O>>[N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:21])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc(-c2ccncc2)cc1
Reactant: CO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccncc2)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Thionyl chloride (683 mL, 9358.59 mmol) was added dropwise over 20 minutes to a suspension of sodium 4-(pyridin-4-yl)benzoate (690 g, 3119.53 mmol) in methanol (15 L) at −10° C., keeping the temperature below 15° C. The mixture was stirred for 10 minutes then heated to 65° C. for 15 hours. The reaction mixture was cooled to 20° C. and the solvent was evaporated. The solid residue was partioned between ethyl acetate (14 L) and aqueous saturated sodium bicarbonate solution (14 L). The organic layer was separated and the aqueous layer extracted with ethyl acetate (7 L). The combined organics were washed with water (14 L), saturated brine (7 L) dried over magnesium sulfate, filtered and evaporated to dryness to afford methyl 4-(pyridin-4-yl)benzoate (570 g, 86%) as a solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:40])[CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1.O>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][O:21][CH3:20])=[CH:29][CH:28]=2)([OH:40])[CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OCOC)cc2)C(CC)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H2O (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts washed with H2O (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated to afford 194 g of 16 that was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.58 (t, J=7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1H), 3.23 (s, 3H), 3.40-3.65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.96-7.06 (m, 3H), 7.17-7.23 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:26]([CH:28]1[CH2:31][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44](Br)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:29]1)#[N:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:26]([CH:28]1[CH2:29][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([C:4]4[C:5]5[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][C:10]=5[N:2]([CH3:1])[N:3]=4)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:31]1)#[N:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 1,6,6-trimethyl-3-tributylstannyl-4,5,6,7-tetrahydro-1H-indazole (110 mg, 0.24 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (95 mg, 0.19 mmol) in DMF (2 mL) were added Pd(PPh3)4 (11 mg, 0.01 mmol) and copper(I) iodide (7 mg, 0.037 mmol). The reaction mixture was heated at 90° C. for 2 h then cooled to room temperature and stirred overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The crude brown oil was purified by silica gel chromatography with 0% to 3% MeOH/CH2Cl2 to afford 43 mg (38%) of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a pale orange foam.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:21])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[C:3]([CH3:21])=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(C)cn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ncc4c3)c(C)cn2c1=O
Yield: 45.5 %

Procedure:
Methyl 8-(1H-indazol-5-yl)-1-cyclopropyl-7,9-dimethyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-7,9-dimethyl-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.17 mmol), and 1H-Indazole-5-boronic acid pinacol ester (48 mg, 0.19 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (30 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:6]([O:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:5]=1)([O-])=O>C(O)C.[Pd]>[O:18]1[CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=3[O:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:11][CH2:12]2)[CH2:19]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-nitro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-4-(oxetan-3-yl)piperazine XXIII (2100 mg, 5.1 mmol) in ethanol (50 mL) was added 10% Pd/C (50% wet, 390 mg dry weight) in a 500-mL Parr hydrogenation bottle. The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken at rt for 2 h on a Parr hydrogenation apparatus. The reaction mixture was filtered, and washed with ethanol. The filtrate was concentrated in vacuo to give 4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)aniline XXIV.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[O-]CC.[ClH:26]>O.C(O)C>[ClH:26].[C:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[C:2]([C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)[OH:10])#[N:22]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccncc1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N#CC(=C(O)c1ccncc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
17.3 g (0.75 mol) of metallic sodium were treated dropwise with 250 ml of absolute ethanol. 75.8 g (0.5 mol) of ethyl isonicotinate and 67.6 g (0.5 mol) of 4-fluorophenylacetonitrile were added to the ethoxide. The reaction mixture was stirred at 100° C. for 15 min. The mixture was then cooled in an ice bath and treated with 600 ml of dist. water. On acidifying to pH 1 using 90 ml of conc. HCl, the title compound deposited as a yellow precipitate. The precipitate was filtered off, washed with dist. water and dried over P2O5 in vacuo. Yield: 85.0 g (62%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:23])[CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C.O>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][O:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc3nc(C)cc(N4CCC(c5ccccc5)C4)c3c2)cc1
Reaction time: 18 h

Procedure:
2-Methyl-4-(3-phenylpyrrolidin-1-yl)quinolin-6-ol (0.05 g; see Example 42 below) was stirred with sodium hydride (60% dispersion in mineral oil; 0.035 g) in DMF (2 mL) for 15 minutes, after which 4-methoxybenzyl bromide (0.12 g) was added. After 18 hours, the reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to give a brown oil. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave the title compound as a cream solid.
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.[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:22].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>>[CH2:28]([N:27]([CH2:26][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:35])[C:15]([CH2:14][O:13][C:10]1[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]=1)=[O:17])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCOC(=O)CCNCc1ccccc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCOC(=O)CCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3-benzylamino-propionic acid ethyl ester 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 colorless oil. MS (ES) for C24H29NO7 [M+H]+: 444.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[N:9]([CH3:27])[C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by methylation of 6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithium bis(trimethylsilyl)amide in THF, followed by quenching with methyl iodide. 1H NMR(CDCl3) d 6.98(s,2H), 4.45(d,1H), 4.3(m,1H), 3.7(s,3H), 2.4(s,3H), 2.3(s,3H), 2.1 (s,6H), 1.5-1.8(m,4H), 1.0(t,6H) ppm.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(OCCN2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(OCCN2CCCC2)c1

Procedure:
A solution of methyl 3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzoate D37 (1.6 g) and sodium hydroxide (708 mg, 18.2 mmol) in MeOH (50 ml) and water (10 ml) was refluxed for 18 hours. The reaction was concentrated and water added and acidified to pH3 with 2M HCl solution. The reaction was concentrated and was added MeOH and was filtered, concentrated to give a brown solid of desired product D38 in 1.5 g. LCMS [MH+] 236.1@0.96 min (5 min run)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(N)cc1)C(=O)OC
Yield: 98.1 %

Procedure:
The compound 2-carbomethoxy-3-(4-nitrophenyl)propanoic acid methyl ester (p-nitrobenzyl malonate dimethyl ester) (2.00 g, 7.55 mmole) was dissolved in 70 ml of ethyl acetate containing 5 percent palladium on carbon (1.0 g - Aldrich Chemical Company) catalyst and was hydrogenated in a Parr shaker employing 50 psig of hydrogen at 22° C. Hydrogen uptake was rapid (15 minutes) and the mixture was maintained under hydrogen pressure for another three hours. The pressure vessel was vented and flushed with nitrogen (N2). The suspension was filtered through a pad of Celite™ and the solvent was removed in vacuo using a rotary evaporator to provide 3-(4-aminophenyl)-2-carbomethoxypropanoic acid methyl ester (p-aminobenzylmalonate dimethyl ester) (1.76 g, 7.41 mmole) as a light yellow oil in 98 percent yield. The structure was confirmed by 1H nuclear magnetic resonance (PMR) and 13C nuclear magnetic resonance (CMR) as well as mass spectroscopy (MS) spectral analysis.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCCC1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26.7 mg, 0.082 mmol) in DMF (1 ml) at 0° C. under nitrogen was added sodium hydride (6 mg, 0.1 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes while allowing it to warm to room temperature. The reaction mixture was then treated with (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene (25 mg, 0.068 mmol) at 0° C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on 12+S Biotage silica column, eluting with ethyl acetate in heptane 0-30% (10CV) and 30% (3CV) to yield the title compound (20 mg, 48%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (m, 4H) 1.2 (m, 2H) 1.46 (m, 1H) 1.57 (m, 2H) 1.61(m, 1H) 1.90 (d, J=12.4, 1H) 3.06 (s, 3H) 4.08 (d, J=7.1, 1H) 4.2 (s, 3H) 4.70 (d, J=15.7, 1H) 4.89 (d, J=15.7, 1H) 7.35 (s, 1H) 7.50 (d, J=7.9, 1H) 7.55 (d, J=7.9, 1H) 7.65 (s, 2H) 7.77 (s, 1H). [α]D20=−26.6 deg (c=13 mg/mL, acetone).
Reaction SMILES: C(O)C.[C:4](=[S:6])=S.[NH2:7][C:8]1[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=1[NH2:14].[OH-].[Na+]>O>[SH:6][C:4]1[NH:7][C:8]2[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: S=C=S
Reactant: COc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(S)[nH]c2c1

Procedure:
70 ml of ethanol and 15 ml of carbon disulfide were added to 2.6 g of 3,4-diaminoanisole and then a solution of 1.5 g of sodium hydroxide in 5 ml of water was added thereto. After heating with a water bath for 3.5 hours, the mixture was cooled with ice, filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was dissolved in ethanol. The solution was filtrated to remove the insoluble matter and then the solvent in the filtrate was distilled off under reduced pressure. The residue was recrystallized from water-containing methanol to obtain 2.0 g of the titled compound (13).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][C:20]([OH:22])=[O:21])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)acetate (2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with ethyl acetate and acidified with 1 M HCl, and then the product was extracted with ethyl acetate and the organic phase was washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness. Yield: 2.0 g (99%)