Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4-phenoxybenzaldehyde (989 mg) and 1-acetylpiperazine (713 mg) were dissolved in 1,2-dichloroethane (11 ml), and sodium triacetoxyboro hydride (1.60 g) and acetic acid (300 mg) were added. The atmosphere was replaced with argon and the mixture was stirred at room temperature for 7 hours. Water (5 ml) and aqueous saturated sodium hydrogen carbonate solution (20 ml) were added and the mixture was extracted 5 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate. Chloroform was removed and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=20:1-10:1) to quantitatively obtain 1.55 g of 1-acetyl-4-(4-phenoxybenzyl)piperazine.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([NH:48][CH3:49])[N:45]=[CH:44][N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH:48][CH3:49])[CH:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: CNc1cc(Cl)ncn1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CNc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)ncn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-6-methylaminopyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.
Reaction SMILES: [C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19]C)=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[OH-].[K+]>CO>[C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([OH:19])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:11])[F:13])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1c(C(=O)O)c(C(F)F)nc(C(F)(F)F)c1C(C#N)=C1CCCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
To a solution of 10.0 g (23.9 mmol) of the compound of Example 2 in 100 mL methanol were added 14.7 g (223 mmol) KOH pellets (85%). The mixture was stirred at room temperature for 3 days and was then partitioned between ether and water. The aqueous layer was acidified with conc. HCl and extracted with ether. The ether layer was washed with brine, dried over magnesium sulfate, and filtered. The filtered. The filtrate was evaporated in vacuo and the residue was recrystallized from ethyl acetate/hexane to yield 8.9 g of the desired product as white crystals, a 93% yield. m.p. 192°-193° C.
Reaction SMILES: [O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Al+3:11].[K+].[Na].[CH:14]([N:16]([CH2:18][CH2:19][CH2:20][P:21](=[O:24])([OH:23])[OH:22])[OH:17])=[O:15].[OH-].[Na+]>>[Al:11].[CH:14]([N:16]([CH2:18][CH2:19][CH2:20][P:21](=[O:22])([OH:24])[OH:23])[OH:17])=[O:15]
Reactant: [Al+3]
Agent: O=CN(O)CCCP(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: [Al]

Procedure:
To an aqueous solution (45 ml.) of potassium alum (9.17 g.) was added mono sodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (3.08 g.) with stirring, and the solution was adjusted to pH 6-7 with 10% aqueous sodium hydroxide solution and then stirred for 2 hours at ambient temperature. The precipitating materials were collected by filtration, washed twice with water (each 10 ml.) and dried to give aluminum salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (2.28 g.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(O)(=O)C(O)=O.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[OH:11])[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C(O)C(=O)O
Product: CC(c1ccccc1)c1c(O)ccc2ccccc12
Temperature: 130 °C
Yield: 86 %

Procedure:
Using a stirred reactor, a mixture of 144 parts of 2-naphthol and 5 parts of oxalic acid is heated to 130° C., while stirring, and 104 parts of styrene are added continuously over one hour. The mixture is then stirred for three hours at 130° C. After completion of the reaction, the mixture is distilled under reduced pressure, giving 213 parts (86% of theory) of 1(α-phenylethyl)-2-naphthol (boiling point 172/176° C./0.2 mbar). The conversion is 90 percent.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[C:10]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][CH:12]=[C:13]([Cl:14])[C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:44]=N/C(OCC)=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[Cl:14][C:13]1[C:4]2[N:3]=[C:2]3[NH:44][CH2:8][CH2:7][N:6]3[C:5]=2[C:10]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][CH:12]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CCO)c12
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[2,4-Dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol (1.41 g, 4.681 mmol) in tetrahydrofuran (18 mL) were added triphenylphosphine (1.84 g, 7.022 mmol), diethylazodicarboxylate (ca. 2.2 mol/L in toluene, 3.19 mL, 7.022 mmol) and phthalimide (1.03 g, 7.022 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the mixture containing the title compound. To a solution of the crude material in tetrahydrofuran (12 mL) and ethanol (1 mL) was added hydrazine monohydrate (2 mL). The reaction mixture was stirred at room temperature for 7 hrs. The precipitate was removed by filtration. The filtrate was concentrated in vacuo, and the residue was recrystallized with ethyl acetate/tetrahydrofuran to give the title compound as a colorless solid (725.5 mg, 2.751 mmol, 59%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.C(N(CCCC)CCCC)CCC.O>CN1C(=O)CCC1>[CH3:21][C:17]1[CH:16]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
tert-Butyl piperazine-1-carboxylate (500 mg) was dissolved in NMP (10 ml), and 4-chloro-2-methylpyridine (685 mg) and tri-n-butylamine (498 mg) were added thereto, followed by stirring at 150° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(2-methylpyridin-4-yl)piperazine-1-carboxylate (667 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[C:16]([O:21][CH2:22]Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:16]([O:21][CH2:22][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)OCCl
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(=O)OCOC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
To a stirred solution of 3,4-dimethoxycinnamic acid (5 g, 24 mmol) and chloromethyl butyrate (3.3 g, 1 eq.) in dry dimethylformamide (20 mL), under nitrogen was dropwise added triethylamine (4 mL, 2.3 g, 1.2 eq). The reaction mixture was heated to 70° C. overnight; during that time a large amount of precipitate formed and TLC (ethyl acetate:hexane 1:2) showed that all the acid had reacted. The precipitate was filtered and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was washed with a small amount of ethyl acetate, and the combined organic phase was washed with water (3×), 5% solution of NaHCO3 (2×), and brine (2×), dried with MgSO4 and evaporated to give crude product as a yellow heavy oil (5.7 g). The crude product was chromatographed on silica gel (200 g, ethyl acetate:hexane 1:3) to give the pure product (second fraction) as a colorless oil (4.7 g, 64% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:9]Br>Br.C(O)(=O)C>[Br:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(O)c(Br)n1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
16.0 g (0.14 mol) of 3-hydroxy-6-methylpyridine are dissolved in 122 ml of 30% strength HBr in glacial acetic acid, and the solution is heated to 70° C. 70.4 [lacuna] (24.3 ml, 0.47 mol) of bromine are added dropwise at this temperature over a period of 1 hour. The reaction solution is stirred at this temperature for another 5 hours. After the reaction is complete, nitrogen is passed through the reaction solution for 2 hours (to drive off bromine). The reaction solution is then concentrated to 50 ml in vacuo. In this manner, an orange-red paste of the hydrobromide of the desired compound is obtained. The hydrobromide is boiled in 400 ml of water and then brought to a PH of 8 with a 1N bicarbonate solution. The dirty brown crude product obtained is recrystallized from water/methanol (2:3), giving colorless crystals of the pure product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](OC)[C:16]=1[N+:23]([O-])=O)(=[O:3])[CH3:2].[CH3:26][OH:27]>[Pd]>[CH3:26][O:27][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]1[N:23]=[C:16]3[C:15](=[CH:14][C:5]=1[N:4]2[C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17]3
Reactant: COc1cccc(C=C2C(=O)c3ccccc3N2C(C)=O)c1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Product: COc1cccc2c1c1nc3ccccc3cc1n2C(C)=O
Reaction time: 3 h
Yield: 53 %

Procedure:
A suspension of 1-acetyl-2-(3-methoxy-2-nitrophenylmethylene)-3-oxo-2,3-dihydroindole from Example 35 (460 mg, 1.36 mmol), 10% Pd/C (70 mg) and MeOH (17 mL) was stirred under H2 at atmospheric pressure (balloon) for 3 hours. Additional Pd/C (70 mg) was added, a fresh balloon of H2 was attached and the mixture was stirred at room temperature overnight. The Pd/C catalyst was filtered over celite and the filtrate was evaporated. The resulting crude yellow product (209 mg, >100%) was purified by LPLC, eluting with CH2Cl2, then CH2Cl2 /EtOAc (3:97), to obtain 208 mg (53%) of the title compound as a colorless solid, Rf 0.47 (hexane-EtOAc 1:1), mp 125.1°-125.8° C.; 1H NMR (CDCl3) δ 9.02 (s, 1H), 8.62 (dd, J=7.6; J=0.8 1H), 8.13 (d, J=8.4, 1H), 7.65 (dt, J=8.0; J=0.8, 1H), 7.59 (d, J=8.4, 1H), 7.53 (m, 2H), 7.11 (d, J=7.6, 1H), 4.18 (s, 3H), 2.97 (s, 3H); 13C NMR (CDCl3) δ 169.8, 155.2, 146.5, 141.4, 138.1, 131.9, 130.5, 128.6, 126.3, 124.3, 124.2, 122.7, 121.6, 120.5, 115.6, 106.7, 56.2, 27.7; MS (EI, m/z) 290 (M+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.CN(C1C=CC=CN=1)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][CH:2]1[CH2:3][CH2:4][O:7][C:6]1=[O:8])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CCO)C(=O)O
Agent: CN(C)c1ccccn1
Product: CC(=O)NC1CCOC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
L-Homoserine (2 mol) was suspended in 900 ml of acetic anhydride and admixed with a spatula tip full of dimethylaminopyridine (DMAP). It was slowly heated to 60° C. After approximately 1 hour, the temperature rapidly increased to 100° C. Subsequently the reaction mixture was stirred at 80° C. for 90 minutes and concentrated to dryness under vacuum. The resultant yellow oil was taken up in isopropanol (600 ml) and allowed to stand overnight at 0° C. The resultant crystals were filtered off, washed with cold isopropanol and dried under vacuum. The yield was 60% N-acetyl-2-amino-4-butyrolactone isolated, the purity 99% (according to HPLC).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:13][N:12]([CH3:14])[CH2:11][C@@H:10]2[OH:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:44]=1)[O:25][CH2:26][C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:44]=1)[O:25][CH2:26][C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:13][N:12]([CH3:14])[CH2:11][C@@H:10]2[OH:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC1(C)OB(/C=C2\c3ccccc3COc3cc(F)ccc32)OC1(C)C
Reactant: CN1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN1C[C@H](Nc2ccc(/C=C3\c4ccccc4COc4cc(F)ccc43)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 82 °C
Yield: 55.8 %

Procedure:
Combine (3S,4S)-4-(4-bromo-2-nitrophenylamino)-1-methylpyrrolidin-3-ol (17.6 mmol, 5.55 g), (E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.0 mmol, 5.62 g), triphenylphosphine (2.87 mmol, 0.75 g), and K2CO3 (44.7 mmol, 6.18 g) in 110 mL of dioxane:water (3:1). Degas the mixture by bubbling with nitrogen for five min, add palladium (II) acetate (0.48 mmol, 322 mg), and heat at 82° C. under nitrogen for 3.5 h. Cool to room temperature, dilute with water and dichloromethane and then pass through a pad of diatomaceous earth. Separate the phases and extract the aqueous phase with dichloromethane twice. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo. Dissolve in 4:1 CH2Cl2/MeOH and pass through a plug of silica using the same solvent. Concentrate the filtrate and triturate with methanol. Collect the resulting solid by filtration to obtain the title compound as a red solid (4.12 g, 56%): 1H NMR (300 MHz, CDCl3) δ 2.23 (dd, J=9.9, 5.6 Hz, 1H), 2.38 (s, 3H), 2.28-2.26 (m, 1H), 2.70 (d, J=3.5 Hz, 2H), 3.36 (dd, J=9.8, 7.1 Hz, 1H), 3.91-3.87 (m, 1H), 4.01 (br s, 1H), 5.00-4.80 (m, 1H), 5.70-5.50 (m, 1H), 6.52 (dd, J=10.3, 2.6 Hz, 1H), 6.68-6.64 (m, 1H), 6.78-6.75 (m, 2H), 7.01 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.24-7.22 (m, 1H), 7.35 (dt, J=7.5, 1.2 Hz, 1H), 7.42 (dd, J=8.7, 6.6 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.94 (s, 1H), 8.00 (d, J=6.2 Hz, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](OCC)=[O:28])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].O>O1CCCC1>[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)CCc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(CCCO)ccc3o2)n1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
Lithium aluminium hydride (0.14 g) was added to a solution of ethyl 3-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]propionate (0.65 g) in tetrahydrofuran (10 ml) at room temperature under an inert atmosphere. After the mixture was stirred for 2 hours, water was added to the mixture. The resulting precipitates were filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]propanol (0.42 g).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:21][CH2:22]O>>[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccncc1
Yield: 86.2 %

Procedure:
Thionyl chloride (1.70 ml, 23.0 mmol) was added to a solution of pyridin-4-yl-acetic acid hydrochloride (2.00 g, 11.5 mmol) in EtOH (30 ml) at 0° C. The reaction mixture was heated to reflux for 18 h, then the temperature of the reaction mixture was brought down to room temperature and the volatiles were evaporated in vacuo. The crude reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with ethyl acetate (2×50 ml), washed with water, brine and dried over anhydrous sodium sulfate. After filtration the organic solvent was evaporated and dried to afford 1.50 g (86.2%) of ethyl 2-(pyridin-4-yl)acetate as pale yellow liquid. This was taken as such for the next step.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([N:14]1[C@H:18]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13].[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([N:14]1[C@H:18]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13]
Reactant: O=C1c2ccccc2CC1CC(=O)N1CSC[C@H]1C(=O)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C([C@@H]1CSCN1C(=O)CC1Cc2ccccc2C1O)N1CCCC1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
Dissolved in 20 ml of methanol were 500 mg of 3-(1-oxo-2-indanacetyl)-4-(R)-(1-pyrrolidinecarbonyl) thiazolidine, and 80 mg of NaBH4 were added to the solution. After stirring the mixture at room temperature, the resultant liquid reaction mixture was concentrated under reduced pressure, and the residue was added with water and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, chloroform was distilled off under reduced pressure to obtain 545 mg of 3-(1-hydroxy-2-indanacetyl)-4-(R)-(1-pyrrolidinecarbonyl)thiazolidine. Thereafter, the process was allowed to progress in accordance with the process of Synthetic Example 1, thereby obtaining the title compound as a diastereomeric mixture. Yield: 87% (amorphous).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14](=[O:19])C(F)(F)F)=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]>O.CCO>[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14]([OH:19])=[O:1])=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]
Reactant: [OH-]
Reactant: CCc1c(C(=O)C(F)(F)F)c2ccc(OC)cc2n1C
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Yield: 65.8 %

Procedure:
KOH (1.9 g, 33.49 mmole) in 20 ml H2O was added to a solution of 1-(2-ethyl-6-methoxy-1-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 73d (2.42 g, 8.47 mmole) in 20 ml EtOH. The reaction mixture was heated to reflux for 8 h and concentrated. The residue was dissolved in H2O, acidified with 1N HCl to pH˜1 and filtrated. The solid was purified by flash column chromatography (2–5% CH3OH in CH2Cl2) to give yellow color solid (1.3 g, 72%). 1H NMR (CDCl3) δ 11.88 (1H, bs), 7.82 (1H, d, J=8.7 Hz), 7.04 (1H, s), 6.77 (1H, d, J=8.7 Hz), 3.80 (3H, s), 3.70 (3H, s), 3.51 (2H, q, J=7.4 Hz), 1.15 (3H, t, J=7.4 Hz). ESIMS (MH+): 234.05.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16]CC.ICC>>[CH2:15]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCI
Product: CCC1c2ccccc2-c2ccccc21
Yield: 97.5 %

Procedure:
Fluorene (5.0 g, 30.1 mmol), n-BuLi (16 ml, 40 mmol, 2.5 M in hexane), RX=iodoethane (7.04 g, 45.1 mmol). 41 was isolated as yellow oil (5.7 g, 97%).
Reaction SMILES: [C:1]([N:4]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[C:1]([N:4]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:61][C@H:59]([C:57]2[NH:56][C:55]3[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=3[N:58]=2)[CH3:60])=[O:16])=[CH:12][C:11]=1[CH3:19])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(C(=O)O)cc1C)C1CCCC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N(c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1C)C1CCCC1

Procedure:
Prepared analogously to Example 1g from 4-(N-acetyl-N-cyclopentylamino)-3-methylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.64 (silica gel: dichloromethane/ethanol=9:1); C24H27ClN4O2 (438.956); mass spectrum: (M+H)+=439/441 (chlorine isotope). Example 314
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][NH2:22]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:22][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole) 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole), and anhydrous tetrahydrofuran (200 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 4 hours. The nitrogen flow was stopped and a solution of methylamine in tetrahydrofuran (36 ml of 1M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered and concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.6 g (74%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.4 g of off-white needles, mp 199°-201° C.