Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:23])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[CH3:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([CH3:13])[C:3](=[O:24])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:11]2=[O:23])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(O)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C2(C)C(=O)Nc3ccccc3C2=O)ccc1O
Yield: 50.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-hydroxy-3-methoxy-phenyl)-propionyl amino]-benzoic acid methyl ester (1.00 g, 3.04 mmol) and LiHMDS (9.12 mmol, 1M solution in THF). After normal workup, the objective compound (0.46 g, 51%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.81 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 5.55 (br s, 1H, OH), 6.76-6.87 (m, 4H, ArH), 7.12 (t, J=7.73 Hz, 1H, ArH), 7.49 (t, J=7.32 Hz, 1H, ArH), 7.90 (d, J=8.12 Hz, 1H, ArH), 8.17 (br s, 1H, NH); m.p. 168-169° C.; MS(EI) m/e 297 [M+], 178, 150; HRMS m/e cacld. for C17H15N1O4 297.1002, found 297.0999.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide (22 mg, 0.06 mmol) in dichloromethane was added acetic anhydride (10 μL, 0.12 mmol), pyridine (15 μL, 0.18 mmol) and DMAP (1.5 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 3 h. Acetic anhydride (2 equiv) and pyridine (3 equiv) were re-filled and the reaction was stirred at room temperature for an additional 1.5 h. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-acetylaminophenyl)benzoxazole-4-carboxamide (11 mg, 44%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.59-9.58 (m, 1H), 8.17-8.16 (m, 3H), 7.77-7.69 (m, 4H), 7.46-7.43 (m, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.40-4.33 (m, 1H), 2.26 (s, 3H), 3.58-3.53 (m, 1H), 3.19-2.88 (m, 3H), 2.13-1.70 (m, 6H); MS (ESI+) m/z 405 (M+H); HPLC 97.3% (AUC), tR=13.85 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)=[CH:5][CH:4]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: CSc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: CSc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylthiophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as pale brown scaly crystals (yield 31%), melting at 172-173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (preparation 9, 0.50 g, 1.58 mmol) and dimethylformamide (10 mL) with sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After 30 minutes, add 1-bromo-2-(2-methoxyethoxy)ethane (0.34 g, 1.88 mmol, Aldrich Chemical Company) and heat two hours at 70° C. Cool the reaction, add water (10 mL) and extract with dichloromethane (100 mL). Wash the organic phase with water, dry (Na2SO4), filter and concentrate the filtrate to afford 4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.62 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([OH:23])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35].O>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([O:23][CH:34]([CH3:36])[CH3:35])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(O)nc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(OC(C)C)nc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the solution of compound 177 in DMF (10 mL) is added anhydrous potassium carbonate (2 eq.) and 2-iodopropane (2 eq.). The resulting mixture is stirred at 60° C. overnight. On cooling the reaction mixture is poured into water (50 mL) and the mixture extracted with dichloromethane, dried over sodium sulfate. The organic solution is concentrated and purified with PTLC to give product 176 as sticky oil. LCMS (M+1) 396.3.
Reaction SMILES: C(NC(C)C)(C)C.[N:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1.[C:16](OCC)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH3:14][C:12]1[CH:11]=[C:10]([CH2:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH:9]=[N:8][CH:13]=1
Reactant: Cc1cncc(C)c1
Reactant: CCOC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cc1cncc(CC(=O)c2ccccc2)c1
Temperature: -5 °C
Yield: 72.5 %

Procedure:
A solution of diisopropylamine (20.2 mL) in anhydrous tetrahydrofuran (180 mL) was cooled to −78° C., and a 1.6 M n-butyllithium-hexane solution (90 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, and then 3,5-lutidine (14 g) was added dropwise. The temperature was raised to −10-0° C., and after stirring for 20 min, a solution of ethyl benzoate (9.8 g) in anhydrous tetrahydrofuran (20 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (10 g, yield 70%).
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3]([C:8]1C=N[C:15]3[C:10](=CC=[CH:13][CH:14]=3)[N:9]=1)[CH2:2]2.ClC1N=C(C)C=C[N:20]=1>>[CH3:13][C:14]1[CH:15]=[CH:10][N:9]=[C:8]([N:3]2[CH2:4][CH:5]3[CH:1]([CH2:7][NH:6]3)[CH2:2]2)[N:20]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Product: Cc1ccnc(N2CC3CNC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4-methyl pyrimidine. MS (ESI) mass calcd. for C10H14N4, 190.25; m/z found 191.2 [M+H]+.
Reaction SMILES: Cl.[O:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:17][C:16]([C:18]4([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.Cl[C:43]([O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:44]>C(Cl)(Cl)Cl.CN(C)C=O>[CH:58]1[C:59]2[CH:47]([CH2:46][O:45][C:43]([N:21]3[CH2:20][CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:16]4[S:17][C:13]([C:10]5[CH:9]=[CH:8][C:7]([C:6]6[O:2][CH:3]=[N:4][CH:5]=6)=[CH:12][CH:11]=5)=[CH:14][CH:15]=4)[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22]3)=[O:44])[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:54]=2[CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a mixture of tert-butyl 2-(7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate hydrochloride (4.2 g) and triethylamine (2.43 g) in a mixture of chloroform (24 ml) and N,N-dimethylformamide (12 ml) was added dropwise a solution of 9-fluorenylmethyl chloroformate (2.28 g) in chloroform (5 ml) under ice-cooling. After being stirred for 30 minutes, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give tert-butyl 2-[4-(9-fluorenylmethoxycarbonyl)-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (5.8 g) as an amorphous powder.
Reaction SMILES: Br[CH2:2][CH2:3]Br.Cl.[CH3:6][O:7][C:8](=[O:15])[C@@H:9]([C:11]([SH:14])([CH3:13])[CH3:12])[NH2:10].N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:12][C:11]1([CH3:13])[S:14][CH2:3][CH2:2][NH:10][C@H:9]1[C:8]([O:7][CH3:6])=[O:15]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1NCCSC1(C)C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5.15 mL (59.8 mmol) of 1,2-dibromoethane in 50 mL of DMF at room temperature was added over 45 min a solution of 10 g (50 mmol) of D-penicillamine methyl ester hydrochloride and 22.5 mL (150.45 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 mL of DMF. The reaction was stirred for 2.5 h, poured into a solution of saturated NaHCO3 and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 8.24 g (87%) of methyl (3S)-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 190.1 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4(O)[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]([C:34]5[CH:39]=[CH:38][C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([C:46]7[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=7)[CH:41]=6)=[CH:36][CH:35]=5)(O)[C:25]5[C:20]4=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:32]5[C:27]([C:26]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[CH:45]=[CH:44][CH:43]=[C:42]([C:46]8[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=8)[CH:41]=7)=[CH:36][CH:35]=6)=[C:25]6[C:20]=4[CH:21]=[CH:22][CH:23]=[CH:24]6)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccc(-c3cccc(-c4ccccc4)c3)cc2)c2ccccc2C(O)(c2ccc(-c3cccc(-c4ccccc4)c3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2cccc(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6cccc(-c7ccccc7)c6)cc5)c5ccccc45)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
9,10-bis(4-(3-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (4.9 g, 7.3 mmole) was suspended in acetic acid (70 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (50 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (4.1 g, 79%) was obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.C(N(CC)CC)C.[C:48]1([SH:54])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O1CCCC1>[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH:26][C:9]2[N:8]=[C:7]([CH2:6][S:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CSc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (400 mg, 0.7 mmol) (Preparation 25), triethylamine (0.2 ml, 1.4 mmol) and thiophenol (100 mg, 0.9 mmol) were dissolved in tetrahydrofuran (3 ml) and the reaction mixture stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1) increasing in polarity to (95:5). This gave the title compound (150 mg) as a foam. MS: 584 (MH+).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH3:5]/[CH:6]=[CH:7]/[CH3:8].[CH2:9]=[C:10](C)C.C=CC=C.CCCC>C1C=CC=CC=1>[CH:2]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: C/C=C/C
Reactant: C=C(C)C
Reactant: C/C=C\C
Agent: C=CC=C
Solvent: c1ccccc1
Solvent: CCCC
Product: CCC(C)c1ccccc1
Reaction time: 24 h

Procedure:
A 1.0 gram sample of an MCM-22 catalyst (65 wt % MCM-22/35% alumina binder) was used for the alkylation of benzene with Raffinate-2 type feed. This is the same catalyst used in Example 1. The Raffinate-2 type feed is a synthetic blend with the following composition: 53.4% cis-butene, 41.2% trans-butene, 4.6% isobutene, 0.5% butadiene, 0.1% n-butane and 0.2% others. The catalyst was in the form of a 1.6 mm ( 1/16″) diameter cylindrical extrudate and was diluted with sand to 3 cc and loaded into an isothermal, down-flow, fixed-bed, tubular reactor having an outside diameter of 4.76 mm ( 3/16″). The catalyst was dried at 150° C. and 1 atm with 100 cc/min flowing nitrogen for 2 hours. The nitrogen was turned off and benzene was fed to the reactor at 60 cc/hr until reactor pressure reached the desired 300 psig (2170 kPa). Benzene flow was then reduced to 7.63 cc/hr (6.67 WHSV) and Raffinate-2 type feed was introduced from a syringe pump at 2.57 cc/hr (1.6 WHSV). The reactor temperature was adjusted to 160° C. Feed benzene/butene molar ratio was maintained at 3:1 for the entire run. Liquid product was collected in a cold-trap and analyzed off line. Butene conversion was determined by measuring unreacted butene relative to feed butene. The catalyst was on stream for 6 days at 1.6 WHSV of butene with 98% 2-butene conversion, 1 day at 4.8 WHSV with 80% conversion, 1 day at 7.2 WHSV with 62% conversion, and followed by 4 days again at 1.6 WHSV with 97% conversion. Representative data are shown in Table 3.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([Cl:28])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:28].[CH3:9][C:10]1[C:11]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(N2CCc3ccccc3[C@@H]2C)nc(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3[C@@H]2C)nc(N(C)c2ccccc2)c1C
Product: Cl
Yield: 44.3 %

Procedure:
After N-methylaniline(0.6 ml, 5 mmol) was added to a mixture solution of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.7 g, 2.4 mmol) prepared in the Step 2 of Example 62 and dimethylformamide(10 ml), 0.42 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and phenylacetyl chloride the title compound was obtained as a light yellow solid (37%), MS: m/e=384 (M+H+).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1.[C:15](=[O:17])=[O:16].O>C1COCC1>[F:6][C:7]1[N:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][C:12]=1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: COc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(F)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL, 385 mmol) at −60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385 mmol) over 5 minutes such that the internal temperature was maintained below −60° C. After stirring for 45 minutes at −65. ° C. a solution of 2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of THF was added over the course of 2 minutes maintaining an internal temperature <−65° C. The reaction was stirred at −70° C. for 1.5 hours then reaction was poured into a 3 L flask containing 1200 g of crushed dry ice. The reaction was allowed to warm to 0° C. and then poured into 1000 mL of water. The organics were removed under reduced pressure and the aqueous layer was acidified with 1100 mL of 2 N HCl. The resulting thick white slurry was stirred for 1 hour then filtered to provide 2-fluoro-5-methoxynicotinic acid as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[O:14][C:11]2[CH:12]=[C:13]3[C:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=2)=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF; 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chlorophenyl isocyanate (411 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 32 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10f as solid. Yield: 520 mg, 71.42%.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O.S(=O)(=O)(O)O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2>C(Cl)(Cl)Cl>[F:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:1][C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2cc(F)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCCc2cc(F)ccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Sodium azide 1.1 g (16.92 mmol) was added to a mixture of 6.0 mL of chloroform and 1.1 mL of water at 0° C. Concentrated sulfuric acid (0.44 mL) was added dropwise and the mixture stirred at 0° C. for two hours then filtered. The chloroform layer containing hydrazoic acid was added to a solution of 1.3 g (7.92 mmol) of 6-fluoro-1-tetralone (prepared by the method of Allinger and Jones, J. Org. Chem., 27, 70-76 (1962)) in 4.8 mL of chloroform. Additional sulfuric acid (2.16 mL) was added dropwise with stirring while maintaining the temperature below 40° C. The mixture was stirred at 40° C. for two hours then at room temperature for 16 hours. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was added to ice; the resulting recipitate was extracted with methylene chloride (5x). The combined extracts were washed with brine, dried over magnesium sulfate and filtered through a silica plug. Solvents were removed under vacuum to afford 162 mg (0.92 mmol, 11%) of the product. 1H NMR (300MHz, CDCl3): 2.21 (m,2H), 2.32 (t,7Hz,2H), 2.7 (t,7Hz,2H), 6.93 (m,3H), 7.8 (br s,1H). FAB-MS: calculated for C10H10FNO 179; found 180 (M+H,100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Br:15][C:16]1[N:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1>>[Br:15][C:16]1[N:17]=[N:18][C:19]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][CH:21]=1
Reactant: Brc1ccc(Br)nn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Br)nn1
Yield: 89 %

Procedure:
As described for example 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (2.46 g, 13 mmol) was converted using 3,6-dibromopyridazine instead of 3,6-dichloropyridazine to the title compound (3.99 g, 89%) as a white solid. MS: m/e=348.0/346.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][O:11][CH3:20])[CH:9]=1
Reactant: CCC1CCCCN1c1ccc(Br)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CCCCN1c1ccc(Br)cc1COC
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of sodium hydride (2.3 g, 93 mmol) in anhydrous DMF (130 mL) was added a solution of [5-bromo-2-(2-ethylpiperidin-1-yl)phenyl]methanol (15 g, 48.3 mmol) in DMF (20 mL) drop wise at 0° C. After 30 minutes, methyl iodide was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), then diluted with water (100 mL) and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (15.2 g, 97%).