Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC=CC1C=CC=CC=1[C:11]1[C:12]2[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(=O)([O-])[O-].[K+].[K+]>CS(O)(=O)=O.ClCCl>[CH:20]1[C:19]2[C:24]3[C:11]([C:12]4[C:17]([C:18]=2[CH:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:14][CH:13]=[C:12]1[C:11]=3[CH:24]=[CH:23][CH:18]=[CH:17]1
Reactant: COC=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
24.0 g of 9-[2-(2-methoxyvinyl)phenyl]phenanthrene and 100 mL of dichloromethane were placed. 6 drops of methanesulfonic acid was added by means of a Pasteur pipette while stirring at room temperature. The stirring was conducted at room temperature for 8 hours. After completion of the reaction, 100 mL of an aqueous 10% potassium carbonate solution was added. An aqueous phase was removed, and an organic phase was washed with saturated saline and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 5.21 g (yield 25%) of benzo[g]chrysene as an intended product was obtained.
Reaction SMILES: F[C:2]1C=CC(O)=C[C:3]=1CO.ICCCCC.[CH3:17][C@@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]=[CH2:37])[CH:31]=[CH:30][C:29]=1[F:38])=[O:25]>>[CH3:17][C@@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:2][CH3:3])[CH:31]=[CH:30][C:29]=1[F:38])=[O:25]
Reactant: OCc1cc(O)ccc1F
Reactant: C=CCOc1ccc(F)c(COC(=O)N2CCNC[C@H]2C)c1
Solvent: CCCCCI
Product: CCCCCOc1ccc(F)c(COC(=O)N2CCNC[C@H]2C)c1

Procedure:
(R)-2-Fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopentane and (R) 2-methylpiperazine resin according to the procedures described for Example 126 to give the product as a yellow oil: δH (400 MHz, DMSO-d6) 0.89 (3H, t, J 7.0 Hz), 1.24 (3H, d, J 7.1 Hz), 1.30–1.45 (4H, m), 1.70 (2H, pent, J 6.7 Hz), 2.90 (1H, m), 3.0–3.20 (4H, m), 3.92 (3H, m), 4.38 (1H, m), 5.07 (1H, d, J 12.5 Hz), 5.12 (1H, d, J 12.5 Hz), 6.93 (1H, m), 6.98 (1H, m), 7.14 (1H, m), 8.90 (1H, br) and 9.40 (1H, br); HPLC (XTERRA, 50/80%, 220 nm) 84.6% (4.85 min).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH2:58])=[CH:52][CH:51]=1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[NH:58][CH2:57][CH2:56][C:53]3[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=3)[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Reactant: NCCc1ccc(F)cc1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCCc3ccc(F)cc3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and 2-(4-fluoro-phenyl)-ethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:16]=2[O:17][CH2:18][C:19](O)=[O:20])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:16]=2[O:17][CH2:18][C:19]([NH:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])=[O:20])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
To a stirred solution of 0.3 g of [2-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid, 0.107 g of glycine ethyl ester hydrochloride and 0.103 g of 1-hydroxybenzotriazole monohydrate in N,N-dimethylformamide were added 0.106 mL of triethylamine and 0.146 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-chloride under ice-cooling, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.33 g of ethyl [2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-acetylamino]acetate
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16]OS(OC)(=O)=O.CCOCC>CC(C)=O.O>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:16])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)O
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To 104 mg (0.49 mmole) of (±)cis-3-oxo-2-pentyl-1-cyclopentaneacetic acid (93:7 cis/trans ratio) in 1 ml of (CH3)2CO there were added, first 56 μl of (CH3)2SO4 (74 ml, 0.59 mmole, 1.2 eq.) and then 81 mg (0.59 mmole, 1.2 eq.) of anhydrous solid K2 CO3. The resulting suspension was heated at r.t. during 4 h and taken in water and with ether. The ether phase was separated and the aqueous phase once more extracted with ether. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated. The residue was distilled in a bulb-to-bulb apparatus (oven t.: 180°/7 Pa) to provide 93 mg (0.44 mmole, yield 84%) of methyl (±)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate (92/8 cis/trans ratio).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N[CH2:14][CH2:15][C:16]([OH:18])=O>C(O)=O>[CH2:5]([N:12]1[C:16](=[O:18])[CH2:15][CH2:14][N:1]2[C:2](=[O:3])[N:4]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:16][CH2:15][CH:14]12)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: NCCC(=O)O
Reactant: NC(N)=O
Solvent: O=CO
Product: O=C1CCN2C(=O)N(Cc3ccccc3)CCC2N1Cc1ccccc1
Reaction time: 15 h

Procedure:
The thiourea group-containing resin of step (C) was treated with formic acid and kept shaking for 15 hrs. The resin was filtered off and the filtrate was concentrated and purified by chromatography (silica gel) to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (S)-(+)-1-amino-2-propanol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.8 min) to provide 2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (19 mg, 0.031 mmol, 44.7% yield) as a mixture of diastereomers: LCMS=489.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.35 Hz), 7.54-7.74 (7 H, m), 5.15 (1 H, s), 3.80-3.92 (1 H, m), 3.12-3.42 (2 H, m), 1.13 (3 H, d, J=4.83 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:9]1[O:11][CH2:10]1.[OH-].[Na+].[CH2:27]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:28]1[O:30][CH2:29]1>C(O)(C)C>[CH2:13]([O:12][CH2:8][CH:9]([OH:11])[CH2:10][S:1][C:2]1[S:3][C:4]([S:7][CH2:29][CH:28]([OH:30])[CH2:27][O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:5][N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Sc1nnc(S)s1
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: CCCCOCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCCCCCCCCOCC(O)CSc1nnc(SCC(O)COCCCC)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole(51.64 grams, 0.34 moles) and isopropanol(150 ml) were added to the reaction flask. Dodecyl glycidyl ether(87.35 grams, 0.34 moles) was slowly added with cooling to maintain the temperature below 25° C. Then sodium hydroxide(0.05 grams) was added followed by butyl glycidyl ether (44.91 grams, 0.34 moles). The reaction mixture was refluxed for 15 minutes and the solvent was stripped off by using a rotary evaporator. The product was characterized by infrared absorption bands at 3200, 2900, 1460, 1385, 1260, 1120, 1050, and 710 cm-1.
Reaction SMILES: [O-2].[O-2].[O-2].[Al+3].[Al+3].O[CH2:7][CH:8]1[CH:13]([CH3:14])[CH:12]2[CH2:15][CH:9]1[CH2:10][CH2:11]2.C=C1C(C)C2CC1CC2>>[CH3:7][C:8]1[CH:9]2[CH2:15][CH:12]([C:13]=1[CH3:14])[CH2:11][CH2:10]2
Reactant: CC1C2CCC(C2)C1CO
Agent: C=C1C2CCC(C2)C1C
Agent: [Al+3]
Agent: [O-2]
Product: CC1=C(C)C2CCC1C2

Procedure:
Next, in an atmospheric reaction tube of a flow type made of quartz and having an outer diameter of 20 mm and a length of 500 mm, 20 g of γ-alumina (N612, manufactured by Nikki Chemical Co., Ltd.) was placed. The dehydration was conducted at a reaction temperature of 285° C. and a weight hourly space velocity (WHSV) of 1.1 hr−1, so that a dehydration product of 2-hydroxymethyl-3-methylbicyclo[2.2.1]heptane containing 2-methylene-3-methylbicyclo[2.2.1]heptane and 2,3-dimethylbicyclo[2.2.1]hept-2-ene was obtained in an amount of 490 g.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:16]>>[C:1]1([CH2:11][C:12]([Cl:16])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Product: O=C(Cl)Cc1cccc2ccccc12

Procedure:
1-Naphthylacetyl chloride is prepared according to the method described in Example 8 using 1-naphthylacetic acid (2.47 g, 13.3 mmol) to give a yellow oil which is dissolved in chloroform (10 mL). This solution is added to a solution of (±)-trans-[2-(4-methyl-1-piperazinyl)]cyclohexanol (2.5 g, 12.6 mmol) in chloroform (10 mL), and the mixture is refluxed for 11 hours under nitrogen. The crude free ester is isolated as described in Example 13, and is converted to the monohydrochloride salt in ether/dichloromethane (35 mL, 6:1) by treatment with 1 equivalent of HCl in the same solvent. The resulting solid is washed with ether and recrystallised from hot ethyl acetate/methanol to yield the title compound.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@@H:53](C)[C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.13 g) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (430 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.42 ml) and the compound (2.26 g), which had been obtained in (2), in anhydrous tetraydrofuran (15 ml) were added. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (2.06 g) was obtained as an amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:13].[N:14]([O-])=[O:15].[Na+].CCOCC>O>[ClH:13].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]=[O:15])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=N[O-]
Reactant: CN1CCCc2ccc(O)cc21
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN1CCCc2cc(N=O)c(O)cc21
Temperature: 4 °C
Yield: 84 %

Procedure:
A mixture of 24.5 g (0.15 mol) of 1-methyl-1,2,3,4-tetrahydro-7-hydroxyquinoline, 75 ml of water and 75 ml of concentrated hydrochloric acid was stirred and cooled in an ice bath to 5°. To this mixture was added dropwise during 40 minutes a solution of 12.42 g(0.18 mol) of sodium nitrite in 50 ml of water while maintaining the temperature between 3 to 5° C. It was occasionally necessary to add a few ml of ether to control foaming. When the addition was complete, the reaction mixture was stirred for 40 min in the ice bath. The solid was collected and rinsed with 2N hydrochloric acid and with ether. It was recrystallized from 700 ml of 2.4 N hydrochloric acid to give 28.7 g (84%) of crude product as brown needles.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.CI.[C:15](OCC)(=O)C>CN(C)C=O.O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH3:15])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCOC(C)=O
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.4 g (12.5 mmol) of sodium hydride is added to 25 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C., and a solution of 1.8 g (11.7 mmol) of 4-chloropyrrolo[2,3-d]pyrimidine in 25 cm3 of dimethylformamide is then added dropwise over the course of 15 minutes. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.12 cm3 (18 mmol) of methyl iodide are then added, and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated out after the phases have settled, washed successively twice with 200 cm3 of water and 200 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa), giving 1.35 g of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in the form of a brown powder. Mass spectrum (DCI): m/e 168 (MH+) (base peak).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:28][CH2:29][CH3:30])[C:17](=[O:27])[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21](OC)=[O:22])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.[OH-:47].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:28]([N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:46][N:45]=[N:44][N:2]=2)=[CH:14][CH:13]=1)[C:17](=[O:27])[CH2:18][C:19]([CH3:25])([CH3:26])[CH2:20][C:21]([OH:22])=[O:47])[CH2:29][CH3:30]
Reactant: [OH-]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)CC(=O)OC
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CC(C)(C)CC(=O)O
Reaction time: 1.5 h

Procedure:
A solution of 3.45 g of 3,3-dimethyl-4-methoxycarbonyl-butanoic acid N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amide and 11.3 g of tributyltin azide in 100 ml of xylene is heated under reflux for 3 hours. 50 ml of 2N sodium hydroxide solution are added and the mixture is stirred at 60° for 90 minutes. After cooling, the aqueous phase is acidified and extracted once with 100 ml and twice with 40 ml each time of CH2Cl2. The dichloromethane phase yields, after drying over Na2SO4 and removal of the solvents, a colourless foam. Purification of the latter by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (95:5) as eluant yields pure 4-carboxy-3,3-dimethyl-butanoic acid N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amide that has an Rf value of 0.44 [CH2Cl2 /CH3OH (4:1)].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][C:19]=2[O:30][CH3:31])[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:32]=[CH:33][CH:34]=[C:9]([Cl:8])[C:10]=2[F:35])[CH2:25]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (89 μl) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (469 mg; prepared as described in Example 45) and diisopropylethylamine (700 μl) in methylene chloride (15 ml) that was cooled to 0° C. The mixture was stirred at room temperature for 2 hours to give 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:9]2([CH3:20])[CH3:19])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:23].[C:27](#[N:29])[CH3:28]>>[C:27]([NH:29][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:9]1([CH3:20])[CH3:19])(=[O:23])[CH3:28]
Reactant: CCOC(=O)N1CC[C@@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=S(=O)(O)O
Reactant: CC#N
Product: CCOC(=O)N1CCC(NC(C)=O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A suspension of (R)-ethyl 4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (322 mg, 1.033 mmol) in acetonitrile (3 mL) was treated with sulfuric acid (0.275 mL, 5.16 mmol), and the resulting clear solution was stirred overnight at room temperature. The reaction was quenched with saturated sodium carbonate, and then extracted 3× with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with ethyl acetate/hexanes (10%-25%-100% EtOAc) to yield the title compound (245 mg, 0.694 mmol, 67.2% yield) as a colorless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1(O)[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:10]1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]([OH:21])[CH2:19][NH:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1)(=[O:12])[NH2:13]
Reactant: NCCCn1nnc2ccccc21
Reactant: NC(=O)C1C=C(C(=O)CBr)C=CC1(O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(O)CNCCCn2nnc3ccccc32)ccc1OCc1ccccc1

Procedure:
A mixture of 17.5 gm of 2-benzyloxy-5-bromoacetyl salicylamide, 17.6 gm of 1-(3-aminopropyl)-1H-benzotriazole, 6 gm of sodium carbonate and 150 ml of ethyl acetate was refluxed for 1.5 hours. After separation of the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in a 100 ml of acetonitrile, and the solution was acidified with 5 gm of oxalic acid. The precipitated 1-[3-(3-carbamoyl-4-benzyloxy-β-oxophenethylamino)-propyl]-1-H-benzotriazole oxalate was collected by suction of filtration converted with aqueous ammonia into the base (m.p. 186°-188° C.) and reduced in 100 ml of ethanol with sodium borohydride to form 1-[3-(3-carbamoyl-4-benzyloxy-β-hydroxyphenethylamino)-propyl]-1-H-benzotriazole.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[C:28]([F:34])[CH:29]=2)=[S:47])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 81%).