Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: Cc1csc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1csc(NCCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2ccnn2C)n1
Reaction time: 2 h
Yield: 5.4 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (68.5 mg, 0.164 mmol) and 2-amino-4-methylthiazole (18.7 mg, 0.164 mmol) in DMA (4 mL) was added NaH (56.3 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a yellow solid (4.0 mg, 5%). LCMS m/z (%)=452 (M+H, 100). 1H NMR (500 MHz, DMSO-d6) δ 10.32 (bs, 1H), 7.89-7.72 (m, 3H), 7.69 (d, J=2.52 Hz, 1H), 7.62-7.56 (m, 1H), 7.48-7.42 (m, 1H), 7.41 (d, J=1.89 Hz, 1H), 7.23 (d, J=9.14 Hz, 1H), 6.45 (bs, 1H), 6.23 (d, J=1.89 Hz, 1H), 4.23-4.18 (m, 2H), 3.70-3.65 (m, 2H), 3.65 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH:11]=[CH:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC=CC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Reaction time: 20 h

Procedure:
To (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester B-2 (2.5 g) in EtOAc (50 mL) is added 10% Pd/C (0.25 g) and the reaction stirred under a hydrogen atmosphere for 20 hours. The suspension is filtered through Celite, washed with EtOAc (3×) and then concentrated in vacuo to afford (2S,3R)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester B-3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)CBr
Reactant: CCCCCN1C(=O)C(c2ccc3c(c2)OCO3)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 3-(1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (1.00 g, 3.10 mmol) and methyl bromoacetate (0.44 mL, 4.60 mmol) in THF (20.0 mL) was degassed by bubbling through argon for one hour. Sodium hydride (0.19 g, 4.60 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 h and quenched with ammonium chloride solution. The mixture was poured into water (150 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.94 g, 76%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.25 (dd, 1H), 7.06 (td, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 6.74-6.65 (m, 2H), 5.90-5.87 (m, 2H), 3.71-3.64 (m, 2H), 3.45 (d, 1H), 3.41 (s, 3H), 3.18 (d, 1H), 1.74-1.60 (m, 2H), 1.39-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3,) δ 177.8, 170.0, 147.9, 147.0, 143.9, 133.1, 131.3, 128.6, 124.6, 122.3, 119.9, 108.7, 108.1, 107.4, 101.2, 52.8, 51.6, 41.8, 40.4, 29.0, 26.8, 22.3, 14.0; MS (ES+) m/z 418.1 (M+23), 396.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH:32]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:32]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: CC(NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccccc1)N(Cc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)Cc1ccccn1
Yield: 50 %

Procedure:
Using general procedure B: Reaction of Pyridine-2-carbaldehyde (22 mg, 0.20 mmol, (1H-Benzimidazol-2-ylmethyl)-{3-[(1-phenyl-ethylamino)-methyl]-benzyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (101 mg, 0.20 mmol) and sodium triacetoxyborohydride (58 mg, 0.26 mmol) in CH2Cl2 (2 mL) at room temperature under N2 for 20 h, followed by purification of the crude material by chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (60 mg, 50%) as a white foam.
Reaction SMILES: [P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].Br[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)n[nH]c2c1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 0.52 g 1-(6-methoxy-1H-indazol-3-yl)-2-methylprop-1-en-1-yl dimethyl phosphate from the Step B above in 10 mL dry DMF. Weigh in 0.626 g cesium carbonate. Add 0.315 g (0.237 mL) 1-bromo-3,3-dimethylbutan-2-one and stir the resulting mixture at room temperature for 2 hours and at 50° C. for one day. Remove half of the DMF under reduced pressure. Dilute the residue with 1:1 MeCN and water, and purify on RP-HPLC using 20-100% MeCN gradient without TFA to give the title compound as a colorless solid. The title compound recrystallizes from 1:1 EtOAc and hexanes. 1H NMR (CDCl3, 500 MHz) δ 7.70 (d, 9.0 Hz, 1H), 6.86 (dd, 2.0 & 8.7 Hz, 1H), 6.48 (d, 2.1 Hz, 1H), 5.33 (s, 2H), 3.87 (s, 3H), 3.57 (d, JP-H=11.4 Hz, 6H), 2.02 (d, JP-H=2.5 Hz, 3H), 1.83 (d, JP-H=3.4 Hz, 3H), 1.32 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CC#N>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: OCCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc(CCCO)c1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (100 g) in MeCN (750 mL) was added K2CO3 (109 g) at ambient temperature. Ethyl bromoacetate (87.4 mL) was added dropwise to the mixture at 0° C. over 30 minutes, and then the mixture was stirred at ambient temperature for 20 hours and at 60° C. for 7 hours. Water (800 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc(1 L) two times. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford ethyl [3-(3-hydroxypropyl)phenoxy]acetate (121 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[S:29]([CH3:28])(=[O:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(S(C)(=O)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of the bis-hydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (50 mg, 0.114 mmol) in pyridine (1 mL) was treated with methanesulfonyl chloride (26 μL, 0.341 mmol) and stirred at room temperature for 16 h. The reaction mixture was evaporated and partitioned between EtOAc (2 mL) and a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 30% then 40% EtOAc/hexane as eluant to afford product as an oil (46 mg, 91%). 1H NMR (CDCl3) 1.60-1.62 (M, 2H), 1.84-1.87 (m, 4H), 1.90-2.04 (m, 2H), 2.55 (s, 3H), 2.76-2.80 (m, 2H), 3.19-3.56 (m, 5H), 3.77 (m, 1H), 3.80 (s, 3H), 4.30 (br t, 1H), 4.71 (m, 1H), 6.42 (br d, J=8.1, 1H), 6.48 (br s, 1H), 6.78 (d, J=8.6, 1H), 7.23-7.36 (m, 5H). LC/MS 7.25 min, [M+1]+ 445.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[O-]CC.[Na+].C(O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:3][CH2:2][C:1](=[O:5])[NH:23]2)=[CH:18][CH:17]=1
Reactant: C=CC(=O)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2ccc(Cl)cc2)N1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
90 g (0.9 mol) of ethyl acrylate are added dropwise at 40°-45° C. to a mixture of 15.9 g (234 mmol) of sodium ethoxide, 110 ml of ethanol, 110 ml of toluene and 25.7 g (180 mmol) of 4-chlorophenylhydrazine and the mixture is subsequently stirred for 1 hour at 40° C. The reaction mixture is evaporated to 100 ml and the residue is taken up in water. The resulting mixture is washed a number of times with toluene and the combined organic phases are extracted with 5% strength NaOH. The combined aqueous phases are adjusted to a pH of 6.5 and cooled to 10° C. The solid formed is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nnc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 54.1 %

Procedure:
To a suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D26) (100 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (121 mg) and tripotassium phosphate (165 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (35.9 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (63 mg) as a yellow solid. MS (ES): C22H21N3OS requires 375. found 376.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:24][CH3:23])=[CH:17][N+:18]([O-:20])=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[3-(6-Dimethylaminomethyl-2-pyridylthio) propylamino]-1-methylthio-2-nitroethene (1.25 g, 0.0037 mol) is added to ethanol (15 ml) saturated with monomethylamine gas at ice bath temperature and is allowed to stir at ambient temperature for 18 hours. The reaction solvent is removed and the residue is chromatographed on silica gel (50 g) eluting with 5-20% methanol/chloroform to 1.1 g of a glassy product.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14]>CN(C=O)C>[CH2:11]([O:12][C:13](=[O:15])[CH2:14][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:10]
Reactant: CC(=O)OCCBr
Reactant: Oc1cccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-hydroxypyridine sodium salt, 6.4 g (36.0 mmol) in 200 mL of DMF was added 3.3 mL (30.0 mmol) of bromoethylacetate. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluent and concentrated to dryness to give 3.8 g (70%) of the desired product as a tan oil. MS (ion spray) 182.1 (M+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]([C@H:16]([NH:15][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: O=C(O)c1cc2ccccc2nc1N[C@H](Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2-chloroquinoline-3-carboxylic acid is reacted with D-phenylalanine to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
Beginning with 15.0 mg 0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) propyl isocyanate, 5.8 mg of the title compound were recovered.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:10]O.C(Cl)(Cl)Cl.O>CC(O)=O>[CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccncc1
Reactant: OO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1cc[n+]([O-])cc1

Procedure:
A solution of 4-isopropylpyridine and 1.5 mL of 30% H2O2 in 7 mL of AcOH was heated at 135° C. A total of 15.4 mL of H2O2 was added in 4 portions, and the solution was refluxed for 2 h. Chloroform and water were added, the layers were separated, and the aqueous layer was extracted 3 times with CHCl3. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% MeOH/CHCl3) provided 139 mg of the 4-isopropylpyridine N-oxide as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: Nc1ccccc1O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-aminophenol.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:6]([OH:8])=O.[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[N:30]=[C:31]([NH2:35])[S:32][C:33]=1[Cl:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[N:30]=[C:31]([NH:35][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:2]=2[F:1])([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH3:9])[S:32][C:33]=1[Cl:34]
Reactant: COC(=O)Cc1nc(N)sc1Cl
Reactant: CC(Oc1ccc(F)cc1F)(C(=O)O)c1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)Cc1nc(NC(=O)C(C)(Oc2ccc(F)cc2F)c2ccc(S(C)(=O)=O)cc2)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.2 %

Procedure:
To a mixture of 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.110 g, 0.22 mmol), (2-Amino-5-chloro-thiazol-4-yl)-acetic acid methyl ester (0.071 g, 0.32 mmol), HOBt (0.052 g, 0.38 mmol), and EDCI (0.074 g, 0.38 mmol) in methylene dichloride (10 ml) was added N-methylmorpholine (0.039 g, 0.38 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile. To give desired compound (0.30 g). 1H NMR (400 MHz, CDCl3): δ 1.45 (t, J=7.2 Hz, 3H), 1.93 (s, 3H), 3.14 (s, 3H), 3.77 (d, J=2.8 Hz, 1H), 4.26 (q, J=7.2 Hz, 1H), 6.69-6.77 (m, 2H), 6.96-7.02 (m, 1H), 7.89 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H); MS (D) m/z: 559.00 (M+1).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH2:24])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25]([CH:30]1[CH2:35][C:34](=[O:36])NC1=O)(OCC)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:19][CH2:20][CH:21]([N:24]1[C:25](=[O:26])[CH2:30][CH2:35][C:34]1=[O:36])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(N)CO
Reactant: CCOC(=O)C1CC(=O)NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 21 %

Procedure:
A mixture of 3.43 g (10 mmoles) of 3-octadecyloxy-2-aminopropanol synthesized according to the method of J. Hajdu et al. [J. Org. Chem., 48, 1197-1202 (1983)] and 1.73 g (10 mmoles) of carboethoxysuccinimide in 50 ml of dichloromethane was stirred, and 1.01 g of triethylamine was added to the mixture under ice-cooling. The resulting mixture was stirred at room temperature for 30 hours and concentrated to dryness. The residue was purified by silica gel chromatography to give 894 mg of the desired 2-succinimidopropane derivative.
Reaction SMILES: OOS([O-])=O.[K+].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:10].[C:20]([C:23]1[C:24]([CH:61]2[CH2:66][CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62]2)=[N:25][C:26]2[N:27]([N:46]=[CH:47][C:48]=2[C:49]2[CH:50]=[N:51][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[C:28]=1[N:29](COCC[Si](C)(C)C)COCC[Si](C)(C)C)(=[O:22])[CH3:21].C1(I)C=CC=CC=1>C(#N)C.O>[NH2:29][C:28]1[N:27]2[N:46]=[CH:47][C:48]([C:49]3[CH:50]=[N:51][C:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[CH:53][CH:54]=3)=[C:26]2[N:25]=[C:24]([CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[C:23]=1[C:20](=[O:22])[CH2:21][OH:10]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: Ic1ccccc1
Solvent: O
Product: Nc1c(C(=O)CO)c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.5 %

Procedure:
A solution of oxone (1.9 g, 3.1 mmol), trifluoroacetic anhydride (1.1 ml, 7.9 mmol) and H2O (5.7 ml) was stirred at 40° C. for 7 h, and then cooled to room temperature. To this a solution of tert-butyl 4-(6-acetyl-7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (0.87 g, 1.13 mmol) and PhI (0.03 ml, 0.23 mmol) in acetonitrile (17 ml) was added. The resulting solution was stirred at 90° C. for 15 h. On cooling, the reaction mixture was filtered and solids were washed with DCM. It was then concentrated in vacuo to give a crude product which was submitted to the analytical group for purification to afford the desired 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyethanone (94.2 mg, 17%).