Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:20]Br.O>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:20]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10.0 g, 59.3 mmol) and triethylamine (18.4 mL, 130 mmol) in acetic acid (30 mL) was slowly added dropwise bromine (3.04 mL, 59.3 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hr and cold water (400 mL) was added. The precipitated solid was collected by filtration, washed with cold water and vacuum dried to give crude ethyl 4-amino-3-bromobenzoate (15.0 g) as red-pink crystals. The obtained crystals were dissolved in ethyl acetate (60 mL), and 4 M hydrogen chloride/ethyl acetate solution was added. The precipitated solid was collected by filtration, washed with a mixed solvent (1:1) of ethyl acetate-diethyl ether, and vacuum dried to give a mixture (8.99 g) of ethyl 4-aminobenzoate hydrochloride and ethyl 4-amino-3-bromobenzoate hydrochloride as colorless crystals. Successively, to a solution of the obtained mixture (1.00 g) in pyridine (12 mL) were added acetic anhydride (0.69 mL, 7.13 mmol) and 4-dimethylaminopyridine (catalytic amount) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction solution was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (758 mg, yield 40%, 3 steps) as colorless crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[C:10](=[O:25])[NH:9][C:8]1=[O:26].[H-].[Na+].[C:29]([O:32][C@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37]I)(=[O:31])[CH3:30]>CS(C)=O>[C:29]([O:32][C@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37][N:9]1[C:10](=[O:25])[C:11]2[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:13]([CH3:16])=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:26])(=[O:31])[CH3:30]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Reactant: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2COC(=O)C(C)(C)C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a stirring solution of 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.65 g, 1.8 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride in one portion. After 30 minutes, (R)-5-acetoxy-1-iodohexane (0.58 g, 2.16 mmol, prepared as above) was added neat. The reaction was allowed to stir at ambient temperature for 20 hours, quenched with water (70 ml) and then extracted with ethyl acetate (3×35 ml). The extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated to give a crude yellow oil. The product was purified by flash chromatography on silica gel (ethyl acetate) to give (R)-1-(5-Acetoxyhexyl)-3-(2-furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.41 g) as a yellow oil. The product oil was dissolved in methanol (20 ml) and treated with a sodium methoxide solution (25 wt. % in MeOH, 0.94 ml, 4.1 mmol). The reaction was allowed to stir at ambient temperature for 48 hours. The solution was diluted with ethyl acetate (40 ml) and quenched with water (20 ml). The organic phase was collected and washed with saturated aqueous sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography on silica gel eluting with 10% methanol-ethyl acetate gave (R)-3-(2furylmethyl)-1-(5-hydroxyhexyl)-8-methylxanthin CT2412R (21 mg) as an off-white solid.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[NH4+].[Cl-].C1C=CC2N(O)N=[N:36]C=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:36])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Boc-Gly-Pro-Nleu-OH (4.1 g, 0.0106 mol.), NH4Cl (1.7 g, 0.032 mol.) and HOBt (1.76 g, 0.013 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. TEA (4.5 ml) was added to the solution slowly while stirring the solution. After a while, EDC (2.6 g, 0.013 mol.) was added to the solution. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 350 ml chloroform. The chloroform solution was washed by H2O 2×20 ml, saturated NaHCO3 2×20 ml, brine 2×20 ml, saturated NaHSO4 2×20 ml and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the product (3.5 g, 84%). TLC Rf=0.36 (developing solvents: CMA, 85:15:3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reaction time: 20 h

Procedure:
2-(4-Trifluoromethoxyphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine-3-sulfonic acid (125 g, 0.78 m) was placed in a 1L, 3-necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330 ml, 3.8 m, 4.5 eq). The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp. approx. 110° C.) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40° C.) and yellow semi-solid residue was diluted with DCM (1 L). The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3-sulfonyl chloride as a pale yellow, oily liquid, 123 g (93% pure; 88% theory). 1H-NMR, CDCl3, (δ): 9.26 (d, 1H), 8.98 (dd, 1H), 8.34 (m, 1H), 7.62 (m, 1H). 13C-NMR, CDCl3, (δ): 155.3, 147.4, 140.9, 134.6, 124.2. MS (m/z): 178.0 [M+1].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:25]([O-])=O)=[C:12]([CH:14]=[CH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][N:17]=3)[CH:13]=2)[CH2:4][CH2:3]1.[Sn].Cl>C(O)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH:15]=[CH:14][C:12]2[CH:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:9]=[CH:10][C:11]=2[NH2:25])=[N:17]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C=Cc3n[nH]c4ccccc34)c2)CC1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1

Procedure:
In a similar manner to Example 2, crude 3-{2-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (262 mg, 0.72 mmol) obtained in Step 1 was dissolved in ethanol (10 mL) and was reacted with tin (0.26 g, 2.2 mmol) and concentrated hydrochloric acid (1.3 mL) at room temperature to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazine-1-yl)phenylamine. In a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazin-1-yl)phenylamine (0.10 g, 0.30 mmol) was dissolved in THF (5.0 mL) and the solution was added with triethylamine (0.13 ml, 0.90 mmol) and 3-methylthiophenecarbonyl chloride (0.05 g, 0.31 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained crude product was triturated in ethyl acetate to obtain Compound 228 (0.10 g, 73%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:39])[NH:22][C:9]4[CH:10]=[C:11]([C:20]#[N:21])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[O:37][N:36]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCOCC5)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example M42) (0.39 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (215 mg, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.ClC(OCC)=O.[NH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]>CN(C)C=O.C(OCC)(=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)#[N:33]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1.13 g (7.68 mmol) of 4-cyanobenzoic acid and 1.6 ml (14.1 mmol) of N-methylmorpholine were dissolved in 30 ml of dimethylformamide. 0.67 ml (7.05 mmol) of ethyl chloroformate was added to the solution under cooling with ice/water. After stirring for 5 minutes, 1.27 g (6.41 mmol) of 3-(2-aminoethoxy)benzonitrile was added to the reaction mixture, and the obtained mixture was stirred at room temperature for one hour. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16])=[O:21]
Reactant: CC1CC(CNc2ccccc2)CCC1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: C1CCOC1
Product: CC1CC(CNc2ccccc2)CCC1NC(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Amino-3-methyl-cyclohexylmethyl)-phenyl-amine (113 mg, 0.52 mmol) in dry THF (5 mL) and TEA (105 mg, 1.04 mmol) is treated with 2-chloro-5-(trifluoromethyl)benzoyl chloride (139 mg, 0.57 mmol). After stirring at RT for 2 hours, the solvent is removed in vacuo and the residue is partitioned between water and DCM. The mixture is passed through a phase separator and the organic portion is concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane:EtOAc (9:1 increasing to 2:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1H, d), 7.82 (1H, d), 7.73 (2H, m), 7.07 (2H, t), 6.56 (2H, d), 6.49 (1H, t), 5.55 (1H, m), 3.93 (1H, m), 2.86 (2H, m), 2.23 (1H, m), 1.88 (1H, m), 1.78 (1H, m), 1.70 (1H, m), 1.59 (2H, m), 1.31 (1H, m), 1.11 (1H, m), 0.92 (3H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:34]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl.CN(C)C=O>[C:34]([O:38][C:39]([CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 991.6 %

Procedure:
To a solution of 2 (6.01 g, 2.0 mmol) in CH2Cl2 (30 ml) and anhydrous DMF (dimethylformamide)(10 ml) at 0° C. was added HOBT (3.16 g, 2.0 mmol), EDC (1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride) (7.19 g, 4.0 mmol) and L-proline-tert-butyl ester (4.22 g, 2.0 mmol). The solution was stirred at 0° C. for 10 minutes, then at room temperature for 5 hours. The solvents were evaporated in-vacuo and the resulting oil dissolved in EtOAc which was washed with H2O (3×200 ml) and brine (200 ml). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. Flash chromatography on silica gel using hexanes/EtOAc (95/5 to 80/20%) afforded the title compound as a colorless oil (8.30 g, 87.5% yield): 1H-NMR (500 MHz, CDCl3) □ 1.04 (s, 9H), 1.45 (s, 9H), 1.89-1.96 (m, 2H), 2.02-2.05 (m, 1H), 2.18-2.22 (m, 1H), 3.65-3.69 (m, 1H), 3.79-3.82 (m, 1H), 4.34-4.37 (m, 2H), 5.03-5.19 (m, 2H), 5.53 (d, 1H), 7.26-7.38 (5H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([CH:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:28]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccccc1Br
Product: CCOC(=O)c1ccccc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
Step (c) of Example 75 was repeated, except that ethyl 2-bromobenzoate and 4-(3,3-diphenyl-1-propyl)piperazine were used. Thus, ethyl 2-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoate was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1>C1(=O)CCCCC1.C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:2]3[CH2:11][CH2:10][CH2:5][CH2:4][CH2:3]3)=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: [Pd]
Solvent: O=C1CCCCC1
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC3CCCCC3)ccc21

Procedure:
Analogously to the method described in Example 14, 4.1 g (20.0 mmol) of compound obtained in Example 4 in 5 ml of cyclohexanone and 150 ml of 95% ethanol are added to 10% Pd—C catalyst and hydrogenated to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CC(=O)CC>[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([O:12][C:4]2[CH:3]=[C:2]([I:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cc(I)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)C1CCC(Oc2cc(I)c3ccccc3c2)CC1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
A mixture of 4-iodo-naphthalen-2-ol (1.0 g, 3.7 mmol) (See, for example, Australian Journal of Chemistry (1963), 16 401-10. b. Journal of the Chemical Society (1943), 468-9, which is incorporated by reference in its entirety), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.8 g, 7.4 mmol) and cesium carbonate (3.6 g, 11 mmol) in tert-butyl alcohol (10 mL) and 2-butanone (7 mL) was heated in a sealed vial at 100° C. for 4 hrs. The mixture was partitioned between water and dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give light yellow precipitate (1.10 g, yield: 73%). ESI-MS: 409.10 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:8][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[N:13]=[CH:12][N:11]=1)[C:4]#[C:5][CH2:6][CH3:7]
Reactant: CCC#CCO
Reactant: C#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(OCC#CCC)ncn1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
In 14 ml of tetrahydrofuran was suspended 0.57 g of sodium hydride (60% in oil), to which 2.5 ml of a tetrahydrofuran solution containing 0.8 g of 2-pentyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 2.5 ml of a tetrahydrofuran solution containing 1.6 g of 4-chloro-6-(2-propynyloxy)pyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 3.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.98 g of 4-(2-pentynyloxy)-6-(2-propynyloxy)pyrimidine (the present compound (5)).
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.B.C1COCC1.Cl>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:3][C@H:2]([NH2:1])[CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2cccnc2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C[C@H](N)Cc2cccnc2)CC1

Procedure:
To a solution of (2R)-2-Amino-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-pyridin-3-yl-propan-1-one (6.23 g; 18.3 mmol, from Example 2) in THF (60 mL) was added, dropwise, BH3.THF (1.0M/THF) (73 mL; 73 mmol). The mixture was stirred at reflux for 2.5 hours, then allowed to stir at ambient temperature overnight. The mixture was cooled to 0–5° C., cautiously treated with 5M HCl (30 mL), stirred at ambient temperature for 4 hours. The mixture was then concentrated on a rotary evaporator to remove THF, diluted with water (30 mL), and the pH adjusted to 10 with concentrated ammonium hydroxide. The product was extracted into ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to yield the title compound as a free base (5.24 g.; 88%). The analytical sample was converted to the hydrochloride salt with ethereal HCl to yield a white crystalline solid, m.p. 168–169° C.; MS (+) ESI, [M+H]+ @ m/z 327; 1H NMR, 400 MHz, DMSO-d6. Analysis for C19H26N4O.HCl.H2O.0.25 C2H6O Calculated: C, 62.21; H, 8.16; N, 14.88 Found: C, 61.72; H, 7.65; N, 14.17.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]2([C:15]3[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:1][C:2]2=[O:3])=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Oc1ccccc1
Product: O=C1Nc2ccccc2C1(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 85 °C
Yield: 82 %

Procedure:
147 g of isatin and 470 g of phenol were brought together and heated to 85° C. Hydrogen chloride gas dried over sulphuric acid is then passed in at 85° C., during which the reaction temperature rises to 115° C. This temperature is maintained and hydrogen chloride is passed in for a further 5 hours. The resulting crystal paste is stirred into 500 ml of benzene and the crystals, colored light yellow, which are thereupon obtained are filtered off and dried. After recrystallization from acetone/chloroform and drying in a water pump vacuum at 90° C., 260 g (82% yield) of colorless crystals are obtained. Melting point 267° C.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([C:21](=[O:38])[NH:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([C:30]([CH3:36])([CH3:35])[CH2:31][O:32][CH2:33][CH3:34])=[C:25]([F:37])[CH:24]=1)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH3:9]>C(OCC)(=O)C>[ClH:1].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([C:21]([NH:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([C:30]([CH3:35])([CH3:36])[CH2:31][O:32][CH2:33][CH3:34])=[C:25]([F:37])[CH:24]=1)=[O:38])[NH:16][CH2:15][CH2:14]2)[CH3:9]
Reactant: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OCC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OCC)ccc32)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution of tert-butyl (R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (320 mg, 0.60 mmol) in ethyl acetate (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected by filtration with hexane to give (R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (273 mg, 0.582 mmol, 97%) as a white solid.