Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[Br:1][C:2]1[S:3][C:4]([CH2:7][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: O=Cc1cnc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ncc(CNc2nccs2)s1
Yield: 51.1 %

Procedure:
A solution of 2-bromothiazole-5-carbaldehyde (150 mg, 0.78 mmol) and 2-amino-thiazole (78 mg, 0.78 mmol) in toluene (7 mL) and 3 Å molecules sieves were stirred at reflux overnight. The strong yellow solution of the corresponding imine was then poured over NaBH4 (147 mg, 3.9 mmol) in hot EtOH (50 mL). The colorless solution was filtered, concentrated and purified by column chromatography (30% AcOEt/PE) yielding N-((2-bromothiazol-5-yl)methyl)thiazol-2-amine (110 mg, 51%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Br:22])=[CH:11][CH:10]=1)([OH:8])[CH3:7])C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:22][C:16]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:6]([OH:8])([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Br)cc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(Br)cc2Br)cc1

Procedure:
1 g. of 3-(2',4'-dibromo-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and 0.5 g. of potassium carbonate in 25 ml. of methanol are heated under reflux for one hour and the mixture is worked up to give 3-(2',4'-dibromo-4-biphenylyl)-3-hydroxybutyric acid, m.p. 118°-120°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[O-]S([O-])(=O)=O.[Ca+2]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: Nc1ccc(CCCC(=O)OCc2ccccc2)cc1

Procedure:
A mixture of 8.14 g (0.455 mol) of 4-(p-aminophenyl)butyric acid, 34.1 ml of benzyl alcohol and 8.65 g (0.455 mol) of p-toluene sulfonic acid hydrate in 115 ml of carbon tetrachloride is heated overnight at reflux with the solvent return through a tower of Drierite (ca. 30 ml of partially powdered indicating Drierite). The partially cooled mixture is diluted to 600 ml with ethyl ether to give a precipitate which is collected to give 4-(4-aminophenyl)butyric acid benzyl ester, p-toluenesulfonate; m.p. 114°-115° C. This is used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:3]=1.[Cl:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)[N:3]=2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C#N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Yield: 85 %

Procedure:
To 3-{[3-amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 2) (7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich) (6.15 g, 28.3 mmol) in pyridine (9.17 mL, 113 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340 g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8CV. Evaporation of the appropriate fractions gave the title compound (11.1 g, 85%) as an off-white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)+.
Reaction SMILES: C(OC(N[C@:7]([CH2:35]CC)([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C@H:18]1[C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=O)CC1C=CC=CC=1)=O)C.[ClH:38].[CH2:39]([O:41][C:42]([NH:44][C@:45](CCC)([C:53](N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH3:40]>>[ClH:38].[CH2:39]([O:41][C:42]([NH:44][C@H:45]([C:53]([C@@:18]1([C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[CH2:15][CH2:7][CH3:35])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH3:40]
Reactant: CCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N
Reactant: CCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Product: CCCN1CCC[C@]1(C(=O)N[C@H](C=O)CCCNC(=N)N)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC

Procedure:
By methods substantially equivalent to those described in Example 37, 0.34 g of EtOCO-Phe(αn-Pr)-Pro-Arg-H.HCl was prepared from EtOCO-Phe(αn-Pr)-Pro-OBzl (TLC Rf =0.67, 50% ethyl acetate:hexanes). EtOCO-Phe(αn-Pr)-Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B), 60 min; to 80/20 (A/B), 300 min).
Reaction SMILES: [F:1][C:2]1[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>C1COCC1.CO.[C].[Pd]>[F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)/C=C/c1c(F)cc2nn(C)cc2c1C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1c(F)cc2nn(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
To a solution of methyl 6-fluoro-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2-methyl-2H-indazole-4-carboxylate (430 mg, 21.47 mmol) in THF/methanol (5 mL/5 mL) was added palladium-carbon powder (86 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (407 mg, yield 94%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[C:27]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][N:38]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][CH2:49][OH:50])[C:43]=4[F:51])[CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])=[CH:26][C:25]2[CH:52]=[CH:53][CH:54]=[CH:55][C:24]1=2.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[S:23]1[C:27]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][N:38]([CH2:41][C:42]4[C:43]([F:51])=[C:44]([CH2:48][CH:49]=[O:50])[CH:45]=[CH:46][CH:47]=4)[CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])=[CH:26][C:25]2[CH:52]=[CH:53][CH:54]=[CH:55][C:24]1=2
Reactant: O=C(c1cc2ccccc2s1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=CCc1cccc(CN2CCC3(CC2)CN(C(=O)c2cc4ccccc4s2)CCO3)c1F
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.282 g) was added to a stirred solution of benzo[b]thiophen-2-yl(9-(2-fluoro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 79, step b) (0.240 g) and trifluoroacetic acid (0.059 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.08 mL) was added, then the solution was dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.24 g. Used directly.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[C:12]1([C:4]2[N:3]=[C:2]([NH:18][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCN(CCC)C(=O)CN
Reactant: Clc1nc(-c2ccccc2)nc2c1CCCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)nc2c1CCCC2
Temperature: 150 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydro-2-phenylquinazoline (1.0 g), 2-amino-N,N-dipropylacetamide (0.78 g) and triethylamine (0.5 g) is refluxed with stirring at 150° C. for three hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (1.3 g), m.p. 87-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O1CCOCC1>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(F)cc1)cn2C
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.17 g, 0.9 mmol), prepared using procedures as described in Example 1, Ag2O (0.22 g, 0.95 mmol), 4-fluoro-benzyl bromide (0.18 g, 0.95 mmol) and dioxane (4 mL) were heated to reflux for 16 hr, then more 4-fluoro-benzyl bromide (90 mg, 0.5 mmol) was added and the solution was heated at reflux an additional 4 hr. After cooling to room temperature, the reaction mixture was diluted with ether (60 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:3) to provide 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (58 mg, 22% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27])(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([NH:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH:24]=[O:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Yield: 42.8 %

Procedure:
A solution of oxalyl chloride (0.45 ml, 4.7 mmol) in dichloromethane (10 ml) was cooled to -78° C. and dimethyl sulfoxide (1 ml) was added dropwise with stirring. After stirring at the same temperature for 2 hours, a solution of 5-acetylamino-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (1.1 g, 4.2 mmol) in dichloromethane (5 ml) was added dropwise and the mixture was stirred for additional 30 minutes. Triethylamine (3.5 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was washed with 1N hydrochloric acid and aqueous saturated sodium bicarbonate solution. The reaction mixture was dried and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the desired compound (0.47 g, yield: 43.1%) as oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH:14]1[C:19]([CH2:20]O)=[CH:18][CH:17]=[C:16]([Cl:22])[CH:15]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])=[CH:14][CH:15]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CON(C)C(=O)c1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1.81 g (10.0 mmol) B5, 1.57 g (11.0 mmol) 4-chlorobenzylic alcohol and 3.03 g (15.0 mmol) tributylphosphine were dissolved in 100 ml tetrahydrofurane and 3.78 g (15.0 mmol) azodicarbonylpiperidine was added at 10° C. The mixture was stirred at room temperature overnight. After removal of the precipitate, the mother liquor was evaporated to dryness and the residue was taken up with ethyl acetate. After filtration and washing with aqueous sodium hydrogen carbonate, 2 N HCl and water, the organic phase was dried over sodium sulfate end the solvent was removed in vacuo. Chromatography of the residue on SiGel (n-heptane/ethyl acetate 2:1) yielded 2.8 g (90%) B8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:25][CH:26](O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:26]([CH3:27])[CH3:25])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NCc2cccc(C)c2O)Cc2ccccc2C1
Reactant: CC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(NCc2cccc(C)c2OC(C)C)Cc2ccccc2C1
Reaction time: 24 h
Yield: 180.8 %

Procedure:
A 100 mL round bottom flask containing the 2-(2-hydroxy-3-methyl-benzylamino)-indan-2-carboxylic acid ethyl ester (364, 1.01 g, 3.10 mmol) is charged with dry tetrahydrofuran (THF, 10 mL). A stirring bar is added and stirring is initiated. After dissolution, iPrOH ([67-63-0], 0.47 mL, 6.21 mmol) and triphenylphosphine ([603-35-0], 1.63 g, 6.21 mmol) are added in turn. After dissolution of the triphenylphosphine, diisopropylazodicarboxylate (1.20 mL, 6.21 mmol) is added. The reaction flask is capped and allowed to stir at ambient temperature overnight. After 24 h, tlc analysis (silica, 1:2 EtOAc/Heptanes) indicates that the starting material is completely consumed and converted to a higher moving spot as visualized by UV. The stirring bar is removed from the reaction flask and the solvent removed under reduced pressure. Pumping to constant weight gives 2.06 g of viscous yellow oil. This is dissolved in DCM (10 mL) and applied to an ISCO Companion which had been fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 60% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 17 mL fractions of UV Active eluent are collected. Fractions 5-14 are combined and evaporated by pumping to constant weight to give viscous residue (0.42 g, 37%).
Reaction SMILES: NC1C=CC(OC)=[C:6]([OH:8])C=1.C[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:6][O:8][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)Nc1ccc(C)c(OCCOc2ccccc2)c1
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NC(C)=O)cc1OCCOc1ccccc1
Yield: 62 %

Procedure:
The compound 19a was prepared starting from 5-amino-2-methoxy phenol (800 mg, 5.75 mmol) according to the procedure described for the synthesis of 18a (as in Example 27) in 62% yield as white powder.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[ClH:17].Cl.[CH:19]([CH:32]1[NH:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CO>[ClH:17].[ClH:17].[CH:19]([CH:32]1[CH2:33][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:35][CH2:36][N:37]1[CH3:1])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCN(C)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (146 mg) was added portionwise to a mixture of 37% aqueous formaldehyde (30 mg) and 3-benzhydryl-1-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]piperazine dihydrochloride in a mixture of dichloromethane (4 ml) and methanol (2 drops) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (60:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-methylpiperazine dihydrochloride (32.9 mg) as a colorless powder.
Reaction SMILES: [Cl-].[Sc+3:2].[Cl-].[Cl-].[CH3:5][N:6]([CH:8]([Li])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]>O1CCCC1>[CH3:5][N:6]([CH:8]([Sc:2]([CH:8]([N:6]([CH3:7])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:8]([N:6]([CH3:7])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: [Li]C(c1ccccc1)N(C)C
Reactant: [Sc+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)C(c1ccccc1)[Sc](C(c1ccccc1)N(C)C)C(c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1.0 g (6.6 mmol) of anhydrous scandium chloride and 10 mL of tetrahydrofuran (THF) were placed in a 100 mL glass vessel to prepare a suspension liquid, which was stirred at room temperature for 1 hour. 2.8 g (20 mmol) of the above-obtained dimethylaminobenzyllithium dissolved in 20 mL of THF was added dropwise thereto, followed by stirring for 12 hours. After completing the reaction, THF was removed, and the target compound was extracted with toluene and then purified by recrystallization to provide 2.4 g of tris(dimethylaminobenzyl)scandium (Sc (CH2C6H4N(CH3)2-o)3) as pale yellow crystals (yield: 80%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19](O)[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([F:21])[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:19][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([F:21])[C:13]=3[C:12]2=[O:22])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2Cc3ccnc(F)c3C2=O)cc1

Procedure:
To a mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1-hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.085 g, 0.28 mmol, Step C) and triethylsilane (0.029 mL, 1.80 mmol) in 6 mL of CH2Cl2 was added TFA (0.62 mL, 7.80 mmol) at RT. The mixture was heated at reflux for 2 h, and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (5 to 10% of EtOAc in CH2Cl2), to yield the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:27][OH:28])=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:28][CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cnc(CO)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-c3cc(Br)co3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 402 (M{81Br}+H+, 100), 400 (M{79Br}+H+, 95).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].[ClH:23].O>C(O)C>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:15])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)NCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.01 h

Procedure:
In 425 ml of ethanol, 64 g of 3-benzyloxyphenacyl bromide and 212 ml of iso-propylamine are stirred at 5° C. under N2 atmosphere, and the temperature is allowed to rise to 12° C. After 0.75 minutes, the clear solution is poured into 2 liters of crushed ice containing 500 ml of concentrated HCl and 1.5 liters of H2O. The mixture is stirred for 20 minutes, filtered and the solid is washed with water to afford 3'-(benzyloxy)-2-isopropylamino-acetophenone hydrochloride, mp 213°-215° C. dec. A 5 g.-sample of this material is stirred in 50 ml of methanol, and the mixture is cooled in ice and neutralized with 10% NaOH until a clear solution is obtained. To this solution, 2 g of NaBH4 is added and after 0.75 hours of stirring, the mixture is evaporated in vacuo, and the resulting solid is collected and washed with H2O. This gives, after drying, 4.4 g of m-(benzyloxy)-β-[(isopropylamino)methyl]benzyl alcohol, mp 83°-85° C.
Reaction SMILES: C(O)C.[Br:4][C:5]1[C:6]([CH3:16])=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([O:11][CH3:12])=[N:9][CH:10]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O-]CC.[K+]>C(OCC)(=O)C.CCOCC>[Br:4][C:5]1[C:6](/[CH:16]=[C:17](\[OH:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([O:11][CH3:12])=[N:9][CH:10]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ncc(Br)c(C)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)/C(O)=C/c1c(Br)cnc(OC)c1[N+](=O)[O-]
Temperature: 45 °C
Yield: 45.6 %

Procedure:
To a solution of ethanol (15 mL) and ether (150 mL) were added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60 mmol), diethyl oxalate (13.15 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol). The reaction mixture was heated at 45° C. for 24 hours. During the reaction, the flask was shaken by hand several times. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-20% ethyl acetate in hexanes to 9.5 g of the title compound (yield 46%).