Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Br-:33].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S+:11]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CC(C)(C)c1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: [Br-]

Procedure:
The intended compound was obtained by a similar manner to that in Synthesis Example 1 except that bis(4-tert-butylphenyl)sulfoxide instead of diphenyl sulfoxide and 4-tert-butylbromobenzene instead of chlorobenzene were used, and the amount of water in the extraction was increased.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2O.C(NC(C)C)(C)C.[Cl:23]CCCl>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(O)c2cc1OC
Reactant: ClCCCl
Solvent: CC(C)NC(C)C
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 6,7-Dimethoxy-quinazolin-4-ol (1.65 g, 8.0 mmol) and phosporousoxychloride (1.52 ml, 16.4 mmol) in 1,2-dichloroethane (16 ml) was added diisopropylamine (3.48 ml, 20 mmol) in a dropwise fashion. The mixture was then heated to 80° C. under an inert atmosphere for 16 hours. After this time the reaction was cooled to room temperature and concentrated in vacuo to dryness, dissolved in CH2Cl2 (50 ml) and washed with sodium bicarbonate solution (5% aqueous, 2*25 ml). The organic layer was separated, dried using MgSO4, filtered and concentrated in vacuo to give a brown residue that was purified by flash chromatography (SiO2) eluted with CH2Cl2:EtOAc—2:98 then 5:95 to give the title compound (1.6 g, 88.9%) as a yellow solid. m/z (LC-MS, ESP): 207 [M+H]+, R/T=3.51 mins
Reaction SMILES: [H-].[K+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[Cl:18][CH:19]=[C:20](Cl)[Cl:21]>O1CCCC1.CCCCCC>[Cl:18][C:19]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:14][CH:13]=1)=[CH:20][Cl:21]
Reactant: [H][H]
Reactant: ClC=C(Cl)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: ClC=C(Cl)Oc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a two-necked, round bottom flask (250 mL) equipped with a magnetic stirrer, pressure equalizing funnel and rubber septum was suspended oil free potassium hydride (2.23 g, 55 mmol, 1.5 eq) in tetrahydrofuran (THF, 25 mL). 4-Phenylphenol (6.30 g, 37 mmol, 1 eq) in THF (50 mL) was then added drop-wise with stirring for over 20 min via the funnel. After the evolution of hydrogen was complete, the orange-yellow slurry was cooled to −78° C., and then treated with drop-wise solution of trichloroethylene (5.8 g, 44 mmol, 1.2 eq) in THF (25 mL) for over 10 min. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature (rt) and then maintained for overnight (12 h). To the dark brown mixture was carefully added water (10 mL) using a syringe and then partitioned between water (200 mL) and ethyl acetate (200 mL). The organic phase was then washed with brine (200 mL). Extraction of the combined aqueous layers was done using ethyl acetate (150 mL×3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using the rotary evaporator to give yellowish brown oil. Silica gel (200 g) column chromatography was done using hexane as eluent to afford 2 (10.5 g, 85%) as colorless oil that later crystallized to white crystals: mp 52-55° C. 1H NMR (300 MHz, CDCl3): 7.62-7.54 (m, 4H, HAr), 7.48-7.41 (m, 2H, HAr), 7.39-7.32 (m, 1H, HAr), 7.18-7.12 (m, 2H, HAr), 6.00 (s, 1H, HC(Cl)═C(O)) ppm; 13C NMR (75 MHz, CDCl3): 153.3, 140.2, 137.8, 128.8, 128.5, 127.3, 127.0, 117.4, 103.9 ppm; IR (cm−1): 3105, 3031, 1898, 1658, 1630, 1603, 1585, 1543, 1310, 1203, 1184, 1107, 1074, 1008, 996, 915, 863, 840, 641, 547, 511; HRMS (ESI) Calculated for C14H10Cl2O [M−H]− 263.0031. Found 263.0030; Elemental analysis Calculated. for C14H20Cl2O.0.02H2O: C, 63.33; H, 3.81. found: C, 63.34; H, 3.79.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[C:5](O)=[O:6].Cl.[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH2:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH:43][C:5](=[O:6])[CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[CH2:3][CH:2]([CH3:29])[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)O)cc1
Reactant: NCC(O)CC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)NCC(O)CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 4-methyl-2-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-pentanoic acid (3.6 g), 4-amino-3-hydroxy-butyric acid benzyl ester hydrochloride (1.6 g), triethylamine (1 ml) and HOBT (1.06 g) in DMF (50 ml) at room temperature was added EDCI (1.63 g). After stirring 16 h the mixture was poured into 1500 ml ice-water and stirred for 20 min. The resulting ppt was filtered and dried to give a creme colored solid. Recrystallization from EtOAc gave 2.1 g of the title compound as a white solid. MS [M+1]+589.2; 1H nmr (400 MHz, DMSO-d6) δ0.73-0.81 (m, 6H), 1.37-1.49 (m, 3H), 2.19 (s, 3H), 2.20-2.28 (m, 1H), 2.46-2.49 (m, 1H), 2.99-3.09 (m, 2H), 3.33 (q, J=13.8 Hz, 2H), 3.90 (m, 1H), 4.19-4.23 (m, 1H), 5.05 (s, 2H), 6.88 (t, 1H), 7.06-7.12 (m, 4H), 7.26-7.34 (m, 6H), 7.75 (d, J=8.1 Hz, 1H), 7.92 (dt, 1H), 8.06 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 9.13 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=[N:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCO
Solvent: CO
Product: O=C(O)c1ccc(N=Cc2cc(Cl)ccc2O)cc1
Yield: 94 %

Procedure:
Using the procedure of Sheeman et al [J.A.C.S., Vol. 84 (1982), p. 2457], 1.37 g of p-amino-benzoic acid, 2.35 g of 5-chlorosalicylaldehyde, 240 ml of ethanol and 17 ml of anhydrous methanol were reacted to obtain 2.59 g of 4-[(5-chloro-2-hydroxy-benzylidene)amino]-benzoic acid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:25][CH3:26])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (650 mg) in tetrahydrofuran (20 mL)-methanol (10 mL) was added 6 mol/L hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1→1/9) to give the title compound as a colorless solid (yield: 227.1 mg, 49%).
Reaction SMILES: [ClH:1].Cl.NCCCC1N=C(N)NC=1.C(OC([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][C:28](=O)[NH:29]C2CCCC2)[N:22]=[C:21]1[NH2:36])=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:23]1[N:22]=[C:21]([NH2:36])[NH:20][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCCC(=O)NC2CCCC2)nc1N
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: NCCCCc1c[nH]c(N)n1
Yield: 18 %

Procedure:
Using the same general procedure as used for the synthesis of 4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16, 12.5 g of lysine methyl ester dihydrochloride 28 afforded 2.25 g (18%) of the target compound 29 as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 6.09 (s, 1H), 4.96 (s, 2H), 2.56 (t, 2H, J=6.3 Hz), 2.27 (t, 2H, J=6.9 Hz), 1.35-1.51 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 149.11, 132.29, 110.59, 40.75, 31.41, 26.62, 26.12; HRMS (ESI) calcd for C7H15N4 (MH+) 155.1291. Found 155.1293.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C@@H:16]1[C@H:21]2[NH:22][C:23](=[O:25])[O:24][C@H:20]2[CH2:19][C@H:18](C(O)C)[C@H:17]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][CH:1]([C@@H:18]1[C@@H:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:21]2[NH:22][C:23](=[O:25])[O:24][C@H:20]2[CH2:19]1)[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(O)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (3.3 g, 32 mmol) was added to a solution of 4 (1.0 g, 2.5 mmol) in pyridine (60 mL) and the solution was stirred overnight at room temperature. The mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column, eluted with 2% MeOH in DCM to give 5 as yellow oil (900 mg, 81%, the ratio of diastereomers is 1:3 by 1H NMR). (ES, m/z): [M+H]+ 457.1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.43 (m, 10H), 4.91-4.95 (m, 1H), 4.72-4.78 (m, 3H), 4.56-4.66 (m, 2H), 4.47-4.50 (m, 1H), 3.61-3.63 (m, 1H), 3.49-3.54 (m, 1H), 3.32-3.35 (m, 1H), 2.03 (s, 3H), 1.51-1.76 (m, 2H), 1.27 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(#N)C.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)OCCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p.=142°-143° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH3:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].CC/C=C/CC>CN1C(=O)CCC1>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC/C=C\CC
Agent: CC/C=C/CC
Solvent: CCC=CCC
Solvent: CN1CCCC1=O
Product: C=CCCCC

Procedure:
The 3-hexene feedstock was assumed to have a composition of 33 wt % cis-3-hexene and 67 wt % trans-3-hexene. The normal boiling points for 1-, 2-, and 3-hexene are listed in Example 2. The normal boiling for NMP, the extraction solvent in this example, is 204° C. (400° F.). The isomerization reaction was assumed to occur at the bottom of the column. The column was assumed to have 150 theoretical stages, a kettle reboiler, and a total condenser. The operating conditions for the column consisted of a pressure of 5 atm, condenser temperature of 124° C. (255° F.), and reboiler temperature of 279° C. (533° F.). In addition, 500 lb/hr of NMP was added to the 10th theoretical stage of the column (near the top). This resulted in a column with a diameter of 11.4 ft and a reflux ratio of 455. For this case, the 1000 lb/hr 3-hexene feed resulted in 980 lb/hr of 99 wt % 1-hexene product. The column bottoms contained 98 wt % NMP, which can be recycled back to the column. A detailed material balance is shown in the following table. RXFEED is the distillation column feed stream, SOLVENT is the NMP extractive distillation solvent stream, BOTTOMS is the distillation column bottoms stream, and 1-HEXENE is the product stream, which is obtained from the top of the column.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:4]#N.S(=O)(=O)(O)O.[OH-:24].[NH4+].[CH2:26]([OH:28])[CH3:27]>>[CH3:2][CH:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:4]([O:28][CH2:26][CH3:27])=[O:24]
Reactant: CC(C#N)C1CCN(Cc2ccccc2)CC1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCOC(=O)C(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 72.7 %

Procedure:
29.2 Parts of α-methyl-1-(phenylmethyl)-4-piperidineacetonitrile monohydrochloride were added portionwise to 166 parts of a sulfuric acid solution 70%. Upon complete addition, stirring was continued for 6 hours at about 150° C. After cooling, 240 parts of ethanol were added and the whole was stirred and refluxed overnight. The reaction mixture was cooled, poured into crushed ice and treated with ammonium hydroxide. The product was extracted with dichloromethane. Th extract was dried, filtered and evaporated, yielding 22 parts (72.7%) of ethyl α-methyl-1-(phenylmethyl)-4-piperidineacetate (int. 32).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C>[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C#N)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc2nc(N3CCC(C(=O)O)CC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
20 ml of ethanol and 2.0 ml of a 1N aqueous solution of sodium hydroxide were added to 318 mg of 2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at 50° C. for 30 minutes and neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration and purified by silica gel column chromatography (chloroform/methanol) to give 116 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Br:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O>[Br:10][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: O=C(O)Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 m mol) in HOAc (10 ml) was added dropwise bromine (2.25 g, 14 mmol) at 10-20° C. for 30 min. The mixture was allowed to warm to room temperature for 3 hours. Then it was diluted with water (100 ml), neutralized to pH=5 with anhydrous sodium carbonate and extracted with EtOAc (100 ml×3). Dried over Na2SO4, filtered and concentrated to afford crude product as brown oil. MS (ESI): m/z 220.9 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 65 h
Yield: 99.8 %

Procedure:
To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (205 mg, 0.40 mmol) in EtOH (10 mL) and AcOH (3 mL) was added 10% Pd/C (40 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (207 mg, quant.). LCMS (method H): RT 2.92 min [M+H]+ 519.4
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[O-][Mo:11]([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[Mo:11]
Reactant: O=[Mo](=O)([O-])[O-]
Agent: CCCCC(CC)CN
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: [Mo]
Temperature: 60 °C

Procedure:
The procedure is as in Example B, but 9.9 g of 98% 2-ethylhexylamine are introduced in the course of 20 minutes into an aqueous solution containing 15.44 g of sodium molybdate and kept at 60° C. After heating at 60° C. for 45 minutes, the mixture is acidified with 23.1 g of 30% sulphuric acid, before washing and drying the product. The latter is in the form of a white solid containing 36.8% of molybdenum and 4.38% of nitrogen.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[N:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]([O:4][CH2:5][Cl:6])=[O:3])[N:10]=1)=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: OCc1cccc(CO)n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCCl)OCc1cccc(COC(=O)OCCl)n1
Yield: 95 %

Procedure:
The reaction of the compound of the formula (II) with the compound of the formula (III) is carried out at a temperature between -30° C. and +10° C., preferably at about -5° C. This reaction will be described in detail hereinafter. At least 2 moles of chloromethyl chloroformate of the formula (III) [as calculated for 2,6-bis(hydroxymethyl)pyridine of the formula (II)] are dissolved in the desired solvent, preferably in chloroform, and a solution containing an organic base, preferably pyridine, in the same molar amount as the compound of the formula (III) in the same solvent is added at a temperature lower than 10° C., preferably at about -5° C., under stirring. The suspension obtained is stirred for about 20 minutes while care is taken to avoid any increase of the temperature. Then, 2,6-bis(hydroxymethyl)pyridine of the formula (II) is added to the above mixture at the same temperature at such a rate that the temperature reaches at most -5° C. The suspension is stirred for about 20 minutes to give a brown solution. After washing this solution with water and evaporation, a practically pure product with 95 to 97% of 2,6-bis(chloromethyloxy-carbonyloxymethyl)pyridine content is obtained. The product obtained after washing with water and making free of the solvent can be used without any purification or, if desired, may be further purified by chromatography on a silicagel column or on an other adsorbent, e.g. on a synthetic resin.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[Cl:23]>CS(C)=O.O.ClCCl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(O)cc1F
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 20 h
Yield: 23.2 %

Procedure:
A solution of 2-fluoro-4-hydroxyaniline (7.1 g) and potassium hydroxide (3.7 g, 85% pure) in dimethylsulphoxide (25 ml) was heated to 80° C. and treated with a solution of 1,2-dichloro-4-(trifluoromethyl)benzene (10.9 g) in dimethylsulphoxide (10 ml). The mixture was stirred at 90°-95° C. for 20 hours, after which time it was diluted with a mixture of water and dichloromethane. The organic phase was dried over sodium sulphate and evaporated down to give 3.6 g of the crude desired product as a brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:21])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]>O1CCCC1.CO.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:21])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)c(F)c2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(C(=O)O)c(F)c2)cs1
Yield: 77.5 %

Procedure:
To a mixed solution of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}-2-fluorobenzoic acid (738.9 mg, 2.412 mmol) in tetrahydrofuran (105 ml), methanol (105 ml) and acetic acid (21 ml) was added 10% palladium carbon (593.0 mg, containing 50% water), and the mixture was hydrogenated at room temperature and atmospheric pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzoic acid (576.2 mg, 1.869 mmol, yield 77.5%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:23][CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 11) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.