Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
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: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 85.2 %

Procedure:
To a solution of 2-bromo-5-nitropyridine (DM) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95° C. for 1 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane→5:95 EtOAc:hexane) to give 5-nitro-2-phenylpyridine (LXXIII) as off-white needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for C11H8N2O2 m/z 200.9 (M+H).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:25][O:24][C:11]1[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2F)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(Oc2ccccc2F)cccc1C(C)C(=O)O
Yield: 73.4 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionate (6.2 g) and potassium hydroxide (2.1 g) in a mixture of ethanol (60 ml) and water (30 ml) was refluxed under heating for 72 hours, and the reaction mixture was evaporated. Water was added to the residue, washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionic acid (3.85 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](C(O)=O)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[C:15]([N:22]1[CH:26]=[CH:25]N=C1)(N1C=CN=C1)=[O:16].NC[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36]C=2)[CH:32]=[CH:31][CH:30]=1>O1CCCC1.CN(C)C=O>[C:25]1([CH2:26][NH:22][C:15]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=2)=[O:16])[C:38]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ncccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)NCc2cccc3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
4.9 g (25 mmol) of 2-ethoxycarbonylpyridine-3-carboxylic acid (N. Finch et al., J. Med. Chem. 1980, 23, 1405) were dissolved in 110 ml of tetrahydrofuran/dimethylformamide (10/1) and treated with 4.5 g (27.5 mmol) of 1,1′-carbonyldiimidazole. After the mixture had been stirred at room temperature for 30 min, 3.9 g (25 mmol) of 1-aminomethylnaphthalene were additionally added and the mixture was stirred at room temperature for a further 72 h. The tetrahydrofuran was then removed in vacuo and the residue was partitioned between 200 ml of ethyl acetate and 200 ml of aqueous sodium hydrogencarbonate solution. The organic phase was additionally washed with water, dried and concentrated in vacuo. 7.9 g (95%) of the product were obtained. 1H-NMR: [lacuna]
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][NH2:26])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1.O>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
Methanesulfonyl chloride (0.186 mL, 275 mg, 2.4 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (0.58 g, 2 mmol) and pyridine (0.32 mL, 0.32 g, 4 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 3 h. Further methanesulfonyl chloride (0.046 mL, 69 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 3 h. Water (1 mL) was added and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and water were added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×20 mL), aqueous sodium hydrogen carbonate (saturated, 2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1) to give the title compound as a colorless solid (344 mg, 47%), δH (250 MHz, CDCl3) 7.33 (2H, m), 7.15 (2H, m), 5.80 (1H, br t, J 4.0 Hz), 4.40 (2H, d, J 4.0 Hz), 3.60 (4H, br t, J 3.4 Hz), 2.88 (4H, t, J 3.4 Hz), 2.82 (3H, s), and 1.49 (9H, s). m/e (ES+) 370 (MH+).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:24][C:25]([NH2:27])=[S:26])[CH3:23]>C(O)C>[CH2:22]([NH:24][C:25]1[S:26][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:27]=1)[CH3:23]
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CCNC(N)=S
Solvent: CCO
Product: CCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.405 g, 1.09 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-ethylthiourea (0.114 g, 1.09 mmol) and the solution was heated to reflux for 14 hours. The reaction was cooled to room temperature and the resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), sodium carbonate solution (10%, 3×20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from methylene chloride and isooctane yielding 2-ethylamino-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.218 g, 53%) as a white powdery crystals: mp 218°-219° C., 1HNMR (DMSO d6) 400 mHz 7.94 (t, 5.38 Hz, 1 H), 7.78 (d, J=8.56 Hz, 2 H), 7.45-7.40 (m, 2 H), 7.37 (d, J=8.56 Hz, 2 H), 7.15 (t, J=9.05 Hz, 2 H), 3.31 (q, J=7.10 Hz, 2 H), 3.18 (s, 3 H), 1.18 (t, J=7.10 Hz, 3 H); MS m/z 377 (M+H). HRMS Δ=0.5 mmu.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]3[NH:11][C:12](=[O:25])[C@H:13]([OH:24])[C@H:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[S:15][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH3:31][N:32]([CH2:34][CH2:35]Cl)[CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:34][CH2:35][N:11]1[C:10]2[CH:26]=[CH:27][C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[S:15][C@@H:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@@H:13]([OH:24])[C:12]1=[O:25]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1

Procedure:
Following a procedure similar to that described in Example 11(d), 3,4 g of (2S, 3S)-2,3-dihydro-8-(4- fluorophenoxy)-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) above] were alkylated with dimethylaminoethyl chloride hydrochloride to give 3.63 g of the title compound as a syrup.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:24])[CH3:20]
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=[CH:17][C:18]=1[Cl:19].C[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[C:21]=2[NH2:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)c(Cl)c3)c2N)cc1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (2.000 g, 13.4090 mmol) and 3,4-dichlorophenylacetonitrile (2.994 g, 16.0909 mmol) in absolute ethanol (30 ml), an ice-cooled solution of sodium methoxide (1.087 g, 20.1136 mmol) in absolute ethanol (20 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜4.5 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as reddish solid (1.536 g, 34% yield). M.p. 189.9-191.3° C. LC-ESI-HRMS of [M+H]+ shows 335.0483 Da. Calc. 335.046642 Da, dev. 4.9 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-:17])(=O)[CH3:15].[K+].C(OC(=O)C)(=O)C.[N:26](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[C:14]([N:1]1[C:2]2[CH:11]=[C:10]([Br:12])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH:13]=[N:26]1)(=[O:17])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Br)cc2c1cnn2C(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 61.5 mmol) in chloroform (150 mL), was added potassium acetate (6.32 g, 64.4 mmol) and acetic anhydride (12.6 g, 122.9 mmol) and reaction mixture was stirred at room temperature for 12 h. After this time, tert-butyl nitrite (25.3 g, 246.1 mmol) and 18-crown-6 (5.7 g, 21.5 mmol) were added and reaction stirred again at 65° C. for 3 h. On completion, the reaction mass was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to afford the title compound (18 g, 98.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1(=O)NC(=O)CC1.[N:21]1([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:24]1[CH2:25][CH2:26][N:21]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:22][CH2:23]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: O=C1CCC(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 24 h

Procedure:
123 Grams of succinimide 3,4-dimethoxybenzoate and 137 mg of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were dissolved in 2 ml of dimethylformamide and stirred for 24 hours. The water was added to the reaction mixture and extracted with chloroform, the chloroform extract was washed with water and a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from ethanol-chloroform to obtain 100 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
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.C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[CH3:34][O:33][C:22]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([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)=[O:28])=[CH:25][CH:24]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 16 h

Procedure:
4.93 g (26.5 mmol) of t-butyl piperazine-1-carboxylate and 4.8 ml (34.5 mmol) of triethylamine were stirred in 50 ml of dimethylformamide under cooling with ice. 5.25 g (26.5 mmol) of monomethyl terephthalate chloride was slowly added to the resultant mixture, and they were stirred for 16 hours. The temperature was elevated to room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate followed by the treatment in an ordinary manner, the title compound was obtained.
Reaction SMILES: [NH2:1]C12CC3CC(CC(C)(C3)C1)C2.N[C:14]1([CH3:24])[CH:21]2[CH2:22][CH:17]3[CH2:18][CH:19](C[CH:15]1C3)[CH2:20]2>>[CH3:15][CH:14]([C@@H:21]1[CH2:22][CH2:17][C@H:18]([NH2:1])[CH2:19][CH2:20]1)[CH3:24]
Reactant: CC1(N)C2CC3CC(C2)CC1C3
Reactant: CC12CC3CC(C1)CC(N)(C3)C2
Product: CC(C)[C@H]1CC[C@@H](N)CC1

Procedure:
From SYNCHEM OHG, Felsberg-Altenburg, D-34587, Germany: 1-amino-3-methyladamantane; 2-amino-2-methyladamantane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2cc(OCc3ccccc3)ccc2c1
Yield: 25.6 %

Procedure:
Prepared according to the method described in Example 24b) from 6-(benzyloxy)-2-naphthol (2.2 g; Chem. Ber., (1965) 98, 1233), (±)-α-(chloromethyl)-3-pyridinepropanol (1.89 g; from Example 24a) above) and sodium hydroxide (0.8 g) in ethanol (30 ml) and water (10 ml) with heating at reflux for 6 hours to give the title compound as a solid (0.9 g).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](OC1C=C(O)C=CC=1OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC(=O)c2ccccc2)cc1O
Reactant: COc1ccc(O)cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2ccccc2)cc1OCc1ccccc1

Procedure:
The compound 3-hydroxy-4-methoxyphenyl benzoate was made as follows. An amount of 2.00 gms. of 3-benzyloxy-4-methoxyphenol, 1.00 gms. of triethylamine and 0.10 gms of 4-dimethylaminopyridine were dissolved in 100 ml. of methylene chloride at 0° C. and stirred. To the mixture was added 1.22 gms. of benzoyl chloride and the mixture was stirred overnight. The mixture was then washed with equal volumes of 1M hydrochloric acid, saturated sodium bicarbonate and water. The mixture was then dried over magnesium sulfate and the solvent evaporated to yield 3-benzyloxy-4-methoxyphenyl benzoate.
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][CH:5]1[CH2:12][NH:13][C:14]1[CH:15]=[C:16]([Cl:27])[CH:17]=[C:18]2[C:26]=1[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1.[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:35](O)=[O:36].C([O-])(=[O:40])C.[NH4+]>>[Cl:27][C:16]1[CH:17]=[C:18]2[C:26](=[C:14]([NH:13][C:12]([CH:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][N:4]3[CH2:3][CH:2]([NH:1][C:35]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][N:29]=3)=[O:36])[CH3:28])=[O:40])[CH:15]=1)[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1
Reactant: CC(N)CN1CC(C)(C)OCC1CNc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: O=C(O)c1cnccn1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: CC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)c1cnccn1
Yield: 62 %

Procedure:
The desired compound was prepared from [4-(2-Amino-propyl)-6,6-dimethyl-morpholin-3-ylmethyl]-(6-chloro-9H-beta-carbolin-8-yl)-amine and 2-pyrazine carboxylic acid following Method E in 62% yield. 1H-NMR (300 MHz, DMSO): δ 12.9 (1H, s), 10.89 (1H, s), 9.42 (1H, s), 9.0 (1H, s), 8.8 (1H, d), 8.6 (1H, d), 8.4 (1H, s), 8.2 (1H, m), 4.5 (1H, m), 4.1 (2H, m), 3.1 (1H, m), 2.1 (4H, m), 1.23 (9H, m). Retention time (LC, method: ammonium acetate standard): 1.69 min. MS (M+): 522.2
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:35](C(OC4C=CC=CC=4)=O)[C:36](=O)[O:37]C4C=CC=CC=4)[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]>CN(C)C=O>[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]4)=[O:37])[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]
Reactant: CCOC(=O)CCCC1CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Ethyl 4-(piperidin-4-yl)butyrate (650 mg, 2.0 mmol, Production example 43-2) was suspended in N,N-dimethylformamide (3.35 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-pyridin-2-yl)-N-(phenoxycarbonyl)carbamate (350 mg, 0.67 mmol, Production example 5-2) was added; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system) to yield the title compound (271 mg, 0.54 mmol, 80%) as a pale yellow oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](N)=[O:7].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[CH3:29][C:30]1([CH2:35][CH2:36][C:37](O)=[O:38])[O:34][CH2:33][CH2:32][O:31]1>ClCCl>[CH3:29][C:30]1([CH2:35][CH2:36][C:37]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:9])=[O:38])[O:34][CH2:33][CH2:32][O:31]1
Reactant: NC(=O)CCC(=O)NO
Reactant: CC1(CCC(=O)O)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(CCC(=O)ON2C(=O)CCC2=O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
N-Hydroxysuccinamide (0.80 g, 6.9 mmol) followed by 4-methylmorpholine (0.70 g, 6.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.32 g, 6.9 mmol) were added to a 0° C. solution of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid (1.00 g, 6.24 mmol) in dichloromethane (12 mL). The solution was allowed to warm to room temperature and was stirred overnight. The reaction mixture was diluted with dichloromethane (10 mL), transferred to a separatory funnel, and washed with water (2×10 mL), saturated aqueous sodium bicarbonate (2×10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.1 g of 1-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]oxy}pyrrolidine-2,5-dione as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1C(Cl)=O.CN([CH:52]=[O:53])C>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:52]([C:44]4[CH:43]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:46][CH:45]=4)=[O:53])[CH2:26][CH2:27]3)=[C:15]2[CH:14]=[N:13]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(OC(F)(F)F)cc5)CC4)ncnc32)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 0.7 mmol) and triethylamine (584 μl). DMF (6 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Trifluoromethoxybenzoyl chloride (180 mg, 0.8 mmol) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.98 (m, 1H), 2.12 (m, 2H), 2.27 (m, 1H), 3.13 (s, 3H), 3.51 (m, 1H), 3.79 (m, 2H), 4.21 (m, 1H), 5.76 (m, 1H), 7.31 (d, 2H), 7.52 (d, 2H), 7.95 (m, 3H), 8.36 (s, 1H), 8.65 (s, 1H). Exact mass calculated for C25H21F4N5O5S 579.12, found 580.2 (MH+).