Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(F)cc3)CC2)C1
Temperature: 120 °C
Yield: 28 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 1-bromo-4-fluorobenzene (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 12% ethyl acetate in hexane), so that the desired product was achieved. Yield: 28%
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(=O)(O)(O)O.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH3:21][CH:22]([C:13]1[CH:14]=[C:9]([CH:2]([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][C:12]=1[OH:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Reactant: C=Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(c1ccccc1)c1ccc(O)c(C(C)c2ccccc2)c1

Procedure:
The reaction was similarly carried out as Example 10 except that into a mixture of 59.5 g of p-(α-methylbenzyl)phenol, 25 g of phosphoric acid and 20 g of acetic acid was poured 31 g of styrene to give only 2,4-di-(α-methylbenzyl)phenol, but scarcely to detect other tert-butylated compounds.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH3:26])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([O:25][CH3:26])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OC)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CO[C@@H]1C[C@H]2[C@H](C(=O)O)[C@H]2[C@]1(N)C(=O)O
Temperature: 23 °C
Yield: 83 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-1) (214 mg, 0.56 mmol) in HOAc (8 mL) and H2O (2 mL) was hydrogenated in the presence of Pd/C (35 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (15 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (10 mL) and propylene oxide (5.6 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-methoxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (I-7) (100 mg 74%) as a white solid. 1H-NMR (250 MHz, D2O) □1.86 (1H, t, J=3.5 Hz), 2.04-2.23 (3H, m), 2.50 (1H, dd, J=12, 7 Hz), 3.29 (3H, s), 3.62 (1H, bt,J=8 Hz); MS[ISN] 214 [(M-H)- ]; mp>250° C.; □D20 -13.84° (c=1.01, H2O).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14]Br)[CH:8]=2)[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6]=[CH:5]2
Reactant: C1CCNC1
Reactant: BrCCOc1ccc2cc(Br)ccc2c1
Product: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
In a flask containing 0.5 g (1.5 mmol) the product from Example 37A, 10 mL of pyrrolidine was added. After stirring at 80° C. for 3 h, the reaction mixture was concentrated under vacuum. The residue was diluted with 100 mL of CH2Cl2 and washed sequentially with water, sodium bicarbonate and brine, dried and evaporated under reduced pressure. Silica gel chromatography (MeOH:CH2Cl2, 95:5) gave the desired material in 98% yield. 1HNMR (300 MHz, CDCl3) δ 1.80 (m, 4H), 2.6 (m, 4H), 2.97 (t, 2H), 4.20 (t, 2H), 2.49 (m, 2H) 7.10-7.90 (m, 6H); MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: [CH2:1]([O:6]N=O)[CH2:2]C(C)C.N[C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.O.C(=O)(O)[O-].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:6][C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:2]
Reactant: CC(C)CCON=O
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
1 ml of isoamylnitrite is added to a suspension of 1 g of 3-amino-β-carboline in 100 ml of ethanol and 2 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for an hour and then refluxed for an hour. As a result, a clear solution is obtained. After cooling, it is poured into a mixture of 100 ml of water and 100 ml of saturated sodium bicarbonate solution. It is extracted three times with 100 ml of ether each time and the evaporation residue of the combined ether extracts is chromatographed (silica gel, methanol/chloroform=95:5) and recrystallized from hexane. Yield: 0.3 g of 3-ethoxy-β-carboline with a melting point of 130°-133° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.CCCCCC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:33](=[O:35])[CH3:34])=[N:11][C:10]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(ncn2COCCOC(C)=O)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
9-(2-Acetoxyethoxy)methylguanine (2 gms, 7.5 mmol) was dissolved in 15 ml of acetic anhydride. The mixture was heated to 120° C. and 0.1 gms (0.8 mmol) of 4-dimethylaminopyridine (DMAP) added. The reaction mixture was kept at 120° C. for 3 hours, then the mixture was cooled to 40° C. and 10 ml of toluene added. Hexane (20 ml) was added slowly to effect crystallization of the product. The solid was collected by filtration and washed with hexane, yielding 1.82 gms of 9-(2-acetoxyethoxy)methyl-N2 -acetylguanine (79%) with a N-9/N-7 isomer ratio of >200:1. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.85 (3H, singlet, --NHCOCH3), 2.08 (3H, singlet, --O2CCH3) , 3.6 (2H, multiplet, --OCH2 --) , 3.95 (2H, multiplet, --CH2O--), 5.4 (2H, singlet, --NCH2O--) , 8.06 (1H, singlet, --N=CH--N--).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:29])[C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([OH:27])[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:28])[CH:16]=1>>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:29])[C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:28])[CH:16]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COC(=O)COc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from methyl 2-bromoacetate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.83 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.73 (s, 2H), 4.66 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H); MS (ESI): 424.8.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32]([C:29]2[N:26]3[C:25]([S:24][CH:28]=[CH:27]3)=[N:31][CH:30]=2)=[O:33])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cnc2sccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=478.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:34]1([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a mixture of indole-5-carboxylic acid (300 mg, 1.86 mmol) and HOBT (278 mg, 2.05 mmol) in dry DMF (10 mL) was added EDAC (464 mg, 2.42 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of TEA (0.78 ml, 5.58 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (473 mg, 2.04 mmol). The reaction mixture was stirred for an additional 16 hrs. To the reaction mixture was added water (25 ml) and the resulting precipitate was filtered and washed with water. The resulting solid was recrystalised from a mixture of EtOH-water (4:1, 10 mL) the precipitate was filtered off, washed with water and dried in vacuo at 40° C. affording 472 mg (67%) of the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:15](=[O:18])(O)[O-].[Na+]>CO>[O:1]1[C:15](=[O:18])[CH2:6][O:5][CH2:4][CH2:3][CH2:2][O:8][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)COCCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C1COCCCOC(=O)COCCCO1
Reaction time: 2 h
Yield: 99 %

Procedure:
271.2 Grams (2.02 moles) of crude 6-hydroxy-3-oxa-caproic acid, as prepared in Example 1, 3.5 liters (87 moles) of reagent grade methanol, and 0.2 grams (2 mmol) of concentrated sulfuric acid were charged into a five liter, round bottom flask containing some boiling chips. A reflux condenser connected to a dry stream of nitrogen gas via tubing was attached, and the solution was heated to reflux with an oil bath for twenty four hours. After the solution had cooled down, 5.00 grams (59.5 mmol) of sodium bicarbonate were added, and a distillation head was attached. The methanol was distilled off at atmospheric pressure. After the methanol was removed, the orangish brown residue was vacuum filtered into a tared, one liter round bottom flask containing a magnetic stirring bar. 297 grams of crude methyl 6-hydroxy-3-oxa-caproate were collected (99.0% yield). A still head was attached, and the crude product was vacuum distilled. Initially, a colorless liquid distilled over between 88° C. and 90° C. (0.01 mm Hg), but the distillation rate eventually slowed down. After two hours, some crystals of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione formed in the condenser. The distillation was stopped. The collection flask was placed in the refrigerator overnight. Crystals of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione formed in the collection flask and were removed by suction filtration. These crystals were washed with 100 mL of ethyl acetate and air dried. 4.11 grams of 1,5,8,12-tetraoxacyclotetradecane-7,14-dione and 67.5 grams of supernatent liquid A were isolated.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1>C(#N)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(F)ccc3n2)cc1
Temperature: 110 °C
Yield: 66 %

Procedure:
439 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 224 mg (corresponding to 2.0 mmol) of 2-amino-5-fluoropyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 302 mg (corresponding to 1.32 mmol) of 6-fluoro-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 7, Step 2).
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14]=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:4]1([CH:2]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[O:15])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCCc2ccccc2)c(O)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1cc(C=O)ccc1OCCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
(1-Bromoethyl)benzene (0.56 mL, 4.13 mmol, 2 eq) was added to a stirred solution of 3-hydroxy-4-(2-phenylethoxy)-benzaldehyde (500 mg, 2.06 mmol, 1 eq) and cesium carbonate (672 mg, 2.06 mmol, 1 eq) in N,N-dimethylformamide (8 mL). The solution was stirred overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with 1M HCl (2×100 mL), and brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel and elution with petroleum ether:ethyl acetate (6:1) gave the product as a colourless oil (680 mg, 95%). RF (petroleum ether:ethyl actetate, 4:1) 0.51. 1H NMR (CDCl3) δ 9.72 (s, 1H, O═C—H), 6.93 (d, 1H, J 7.9 Hz, ArH), 5.38 (q, 1H, J 6.4 Hz, CHCH3Ph), 4.33 (m, 2H, CH2CH2Ph), 3.21 (t, 2H, J 6.8 Hz, CH2CH2Ph), 1.67 (d, 3H, J 6.4 Hz, CHCH3Ph).
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26]([F:29])([F:28])[F:27].[OH-:30].[Na+].OO>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:30])=[CH:22][CH:23]=2)=[CH:13][C:12]=1[C:26]([F:27])([F:28])[F:29]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
9-BBN (158 mL, 79 mmol) was added to a solution of 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxyl)benzene (15.75 g, 52.7 mmol) in THF (160 mL) at 0° C. The resultant reaction mixture was stirred at room temperature overnight. To the mixture was added water (16 mL), 3M NaOH solution (80 mL) and 30% hydrogen peroxide (80 mL). It was stirred at 50° C. for 2 h, concentrated in vacuo, and diluted with ethyl acetate (200 mL). The organic phase was collected, washed with water (100 mL×2) & brine (100 mL), dried over sodium sulfate, and concentrated. Purification via a column chromatography then provided the title compound as a colorless oil (12.13 g, 71.7% yield). LCMS: rt=2.08 min, [M+H+]=299
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].II.[I:19](O)(=O)=O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([I:19])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c(I)c(OC)ccc12

Procedure:
The process for the key intermediate in the copending application is exemplified as follows: 6-methoxy-1-naphthalenecarboxylic acid methyl ester is reacted with iodine and iodic acid in the presence of 98% sulfuric acid to give 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester, which in turn is reacted with trifluoromethyl iodide and copper powder in a stainless steel autoclave to give 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester. Hydrolysis of the latter compound with dilute aqueous sodium hydroxide gives 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid, one of the key intermediate noted hereinbefore. The latter compound also can be named 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[OH-].[K+].[C:33](Cl)(Cl)=[O:34]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 g of 1-benzyl-4-(2-anilino-ethylamino)-piperidine and 2000 ml of toluene and 1940 ml of potassium hydroxide solution are charged into a reaction vessel. The temperature is kept between 5° and 10° C. with a mixture of ice and methanol while 300 g of phosgene are introduced in the course of 3 hours. Thereafter the reaction mixture is stirred for 2 hours at room temperature. During the dropwise addition of 860 ml of potassium hydroxide, the temperature is kept below 25° C. with an ice-bath. The batch is then stirred for 14 hours. The precipitated crystals are collected with suction and dried. The two-phase filtrate is separated in a separating funnel. The toluene phase is dried over 200 g of sodium sulphate, filtered and concentrated. The residue is recrystallised from 400 ml of ethanol to give the 1-(1-benzyl-4-piperidyl)-3-phenyl-imidazolidin-2-one with a melting point of 173°-174° C. A mixture of 151 g of 1-(1-benzyl-4-piperidyl)-3-phenylimidazolidin-2-one, 1100 ml of methanol, 45 g of hydrochloric acid (chemically pure), 500 ml of water and 15 g of palladium on charcoal catalyst is hydrogenated at 30°-35° C. and under normal pressure until the theoretical amount of hydrogen has been taken up. The catalyst is removed by suction filtration and the filtrate is concentrated by rotary evaporation. The residue is dissolved in 200 ml of water, the solution is made alkaline with 100 ml of conc. ammonia (minimum pH 12) and extracted with five 300 ml portions of methylene chloride. The purified extracts are dried over Na2SO4 and concentrated. The residual colourless oil crystallises after some time. The 103 g of crystalline substance are dissolved in 600 ml of ethyl acetate under reflux, insoluble material is filtered off hot and the filtrate is concentrated by rotary evaporation to a volume of approx. 500 ml and allowed to crystallise. White crystals of 1-(4-piperidyl)-2-phenyl-imidazolidin-2-one with a melding point of 123°-125° C. are obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[O:10])=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([O:22][CH3:21])=[CH:7][N:6]=1)=[O:10]
Reactant: C[O-]
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(Br)cn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cnc(NC(=O)Nc2cc(C)ccc2OC)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 13 %

Procedure:
To a stirred solution of 1-(5-bromo-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (47 mg; 0.14 mmol) in N-methyl pyrrolidinone (300 μL) was added sodium methoxide (0.5 mmol). The reaction was heated to 100° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), brine (30 mL), then dried (MgSO4), and filtered. The crude product was purified using a 0.5 mm prep plate eluting with hexane and ethyl acetate (1:1) to yield a yellow solid (13% yield). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 6.80 (dd, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 2.38 (s, 3H). LRMS (ESI, Positive) m/e 289.10 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.S.[K].[S:18]1C2C=CC=CC=2N=C1.Cl>C(O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([SH:18])[S:3][C:4]=2[CH:10]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: c1ccc2scnc2c1
Agent: Cl
Agent: S
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(S)sc2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g, 6.64 mmol) from Step 2 was suspended in absolute ethanol (35 mL) and treated with potassium hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 80° C. The benzothiazole starring material gradually went into solution. After hearing for 30 minutes, the mixture was cooled in an ice bath, treated with 1N hydrochloric acid (13.5 mL), and evaporated under vacuum. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the aqueous phase extracted with more ethyl acetate (50 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under vacuum to a yellow-tan solid (1.56 g). This material was triturated with diethyl ether and dried under vacuum to provide 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g) as a pale tan powder.