Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=CC([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.2 mL, 1.36 mmol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1 H, J=6.9 Hz), 6.35 (s 1 H), 4.83–4.78 (m, 1 H), 3.14–3.09 (m, 1 H), 2.88 (s, 6 H), 2.80–1.25 (m, 13 H), 0.085 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D−15.17 (CH2Cl2, c=0.145).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cc1

Procedure:
1-fluoro-4-nitrobenzene (133 mg, 0.94 mmol), bis(2-methoxyethyl)amine (125 mg, 0.94 mmol) and potassium carbonate (143 mg, 1.04 mmol) were stirred in DMSO (2 mL) at 70° C. for 24 hours. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound. MS (ESI+) m/e 255.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][C:33](C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH3:33])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: [Li]C(C)(C)C
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 1.6 mmol, Preparation #5, Step A) in THF (12 mL) was cooled to about −75° C. then t-BuLi (1.7 M in hexanes, 1.05 mL, 1.79 mmol) was added keeping the temperature about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. Additional t-BuLi (1.7 M in hexanes, 0.286 mL, 0.487 mmol) was added and the mixture was stirred an additional 15 min. The mixture was treated with MeI (0.461 g, 3.24 mmol) then the temperature of the mixture was raised to about 15° C. over about 10 min. The mixture was stirred at about 20° C. overnight then saturated aqueous NH4Cl (5 mL) was added. The mixture was stirred for about 15 min at about 20° C. then the material was partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography with a 25 g silica gel column and eluted with 0 to 40% EtOAc/heptane to provide 2-bromo-7-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.54 g, 66%): LC/MS (Table 2, Method g) Rf=2.25 min; MS m/z 504, 506 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:36]=[O:37]>>[CH2:1]([O:8][C:9]1[NH:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)([CH:36]=[O:37])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(OCc2ccccc2)cc1-c1ccc2c(c1)OCCO2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1NC(OCc2ccccc2)=CC1(C=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-5-(2,3-dihydrobenzo-[1,4]dioxin-6-yl)-1-isopropyl-1H-pyrazole (1.8 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.97 g) at 80° C., and the mixture was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, a sodium hydroxide aqueous solution (2 mol/L, 10 mL) was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:hexane/dichloromethane=1/4-dichloromethane) to give the title compound (0.86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(OCC)(O[CH2:21][CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(Cl)c1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Into a 500 ml four-neck flask were charged 26.5 g (0.11 mol) of (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoic acid obtained in Step 1, 260 ml of dimethylformamide (DMF), 24.7 g (0.16 mol) of diethyl sulfate, and 30.4 g (0.22 mol) of potassium carbonate under a nitrogen atmosphere, followed by 2 hours of reaction at 35 to 45° C. After completion of the reaction was confirmed by HPLC analysis, a mixed solution of 3.6 g (0.06 mol) of acetic acid/3.6 g of DMF was added dropwise and the whole was stirred at 30 to 35° C. for 1 hour to decompose excess diethyl sulfate. Thereafter, extraction with a mixed solution of 400 ml of ethyl acetate/400 ml of water/23.4 g of hydrochloric acid was conducted and the organic layer was washed twice with 400 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 9 ml of ethanol, and 19 ml of water to obtain 25.4 g (yield 86.0%) of the aimed compound as light yellow crystals. The total yield from 1-chloro-2-methoxybenzene was 52.0% and the purity was found to be 99.6%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:25][N:26]([CH:30]1[CH2:36][CH2:35][CH2:34][NH:33][C:32]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:31]1=2)[C:27](=[O:29])[CH3:28]>ClCCl>[C:1]([N:33]1[CH2:34][CH2:35][CH2:36][CH:30]([N:26]([CH2:25][C:24]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:22]([C:21]([F:20])([F:49])[F:50])[CH:23]=2)[C:27](=[O:29])[CH3:28])[C:31]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Reaction time: 15 h
Yield: 71.7 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by dimethylaminopyridine (cat.) and pyridine (0.3 mmol) to a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.05 g, 0.11 mmol) in dichloromethane (1 ml). After stirring for 14-16 h dilute with dichloromethane (2 mL) and wash with 5% HCl (2 mL), water (2 mL) and brine (2 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This afford the title compound (0.04 g, 89%) as a colorless solid: MS (ES+): 507 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH2:43])=[N:40][N:39]=1>C(#N)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH:43][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][C@@H:11]3[CH2:10][CH2:9][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[N:16][CH:17]=2)=[O:21])=[N:40][N:39]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cn2)CC1
Reactant: Nc1nnc(Cc2cccc(Cl)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cccc(Cl)c4)s3)cn2)CC1
Reaction time: 96 h

Procedure:
0.321 g of cis-6-(4-tert-butoxycarbonylcyclohexyloxy)nicotinic acid (1 mmol, 1 eq.) is placed in 50 mL of acetonitrile at room temperature. 0.33 mL of diisopropylethylamine (2 mmol, 2 eq.), 0.466 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1 mmol, 1 eq.) and 0.270 g of 5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylamine (1.2 mmol, 1.2 eq.) are successively added with stirring. After 4 days at room temperature, the reaction medium is evaporated and 15 mL of DMF are added. The medium is stirred again for 18 hours, diluted in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 5% to 50%. After evaporating the fractions of interest, the residue is chromatographed on silica gel with a gradient of ethyl acetate in dichloromethane ranging from 2% to 20%. 0.262 g of tert-butyl cis-4-{5-[5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]pyridin-2-yloxy}cyclohexanecarboxylate is obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([O:8][C:3]2[C:2]([C:21]3[CH:20]=[CH:19][C:18]([C:32]4[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=4)=[C:17]([F:16])[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: N[C@H]1CC[C@H](Oc2ncccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3O[C@H]3CC[C@H](N)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using trans-4-((3-bromopyridin-2-yl)oxy)cyclohexanamine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H22FN5O, 379.18; m/z found, 380.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.1, 2H), 8.15 (dd, J=4.9, 1.7, 1H), 7.81 (dd, J=7.4, 1.7, 1H), 7.53 (m, 3H), 7.05 (dd, J=7.4, 5.0, 1H), 6.87 (s, 2H), 5.02 (m, 1H), 2.63 (m, 1H), 2.05 (m, 2H), 1.77 (m, 2H), 1.39 (m, 2H), 1.18 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]=2.[H][H]>CCO.[Pd]>[OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(/C=C/c3ccccc3)ccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(CCc3ccccc3)ccc2C1=O

Procedure:
(E)-tert-butyl 2-(2-hydroxy-1,1-dimethyl-4-oxo-7-styryl-1,4-dihydronaphthalene-3-carboxamido)acetate (150 mg, 335 μmol, Example 108) was dissolved in EtOH (3352 μL). Palladium (10% on carbon, 35.7 mg, 335 μmol) was added, and the reaction mixture was placed under one atmosphere of hydrogen with a balloon for 2 hours. The reaction mixture was filtered through a pad of Celite, washed with DCM, and concentrated to give the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: O=C1Cc2cc(I)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(I)cc32)c(C)c1CCC(=O)O
Yield: 71.1 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 130 mg 5-iodo-2-oxindole, and 75 μL of piperidine in 3 mL of ethanol were stirred at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 155 mg of the title compound (71%) as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]3[NH:28][C:27](=[O:29])[NH:26][N:25]=3)[N:15]=2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1>Cl>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]3[NH:28][C:27](=[O:29])[NH:26][N:25]=3)[N:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cc3ccccc3c(O[C@H]3CCNC3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude (S)-tert-butyl-3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)-pyrrolidine-1-carboxylate (1 g, 1.258 mmol) was dissolved in a solution of 4N HCl in dioxane (0.315 mL, 1.258 mmol) and stirred at RT for 30 minutes. The solvent was removed in vacuo and the resulting oil was dried under high vacuum to give the title compound, which used without further purification. ESI-MS m/z [M+H]+ 298.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:11])=[CH:8][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)benzoic acid (Preparation 148,150 mg, 0.54 mmol) in dichloromethane (25 mL) was added methanesulphonamide (153 mg, 1.61 mmol), 4-dimethylaminopyridine (196 mg, 1.61 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (307 mg, 1.61 mmol) and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with dichloromethane, washed with water and 1M hydrochloric acid solution, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with 95:5 dichloromethane:methanol to afford the title compound (102 mg, 53%).
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1.[H-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([O:6][CH:4]2[CH2:5][N:2]([CH3:1])[CH2:3]2)[N:9]=1
Reactant: CN1CC(O)C1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(Oc2cncc(Cl)n2)C1

Procedure:
2-chloro-6-((1-methylazetidin-3-yl)oxy)pyrazine (129) was prepared by reacting 1-methylazetidin-3-ol (50 mg, 0.336 mmol, 1 eq) and 2,6-dichloropyrazine (32) (29.2 mg, 0.336 mmol, 1 eq) in DMF (5 mL) and sodium hydride (16.11 mg, 0.671 mmol, 2 eq) under refluxing temperature for 8 hrs.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>C(OCC)(=O)C.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cn2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(Cl)cn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to column chromatography (ethyl acetate/heptane (1:5) (85%, white solid). HPLC-MS: m/z=355.1 (M+1); Rt: 4.56 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]1=[S:12])[CH3:2]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C)c1N1C(=O)CN(C(C)C)C1=S
Yield: 47.1 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (13.0 g) as a light yellow solid, m.p. 132°-134° C. Anal. Calcd. for. C15H20N2OS: C, 65.18; H, 7.29; N, 10.14. Found: C, 65.06; H, 7.37; N, 10.20. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(O)(=O)C(O)=O.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[OH:11])[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: C=Cc1ccccc1
Agent: O=C(O)C(=O)O
Product: CC(c1ccccc1)c1c(O)ccc2ccccc12
Temperature: 130 °C
Yield: 86 %

Procedure:
Using a stirred reactor, a mixture of 144 parts of 2-naphthol and 5 parts of oxalic acid is heated to 130° C., while stirring, and 104 parts of styrene are added continuously over one hour. The mixture is then stirred for three hours at 130° C. After completion of the reaction, the mixture is distilled under reduced pressure, giving 213 parts (86% of theory) of 1(α-phenylethyl)-2-naphthol (boiling point 172/176° C./0.2 mbar). The conversion is 90 percent.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[N:4]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:3]1.[CH2:24]1[O:32][C:31]2[C:26](=[CH:27][CH:28]=[C-:29][CH:30]=2)[O:25]1.[Mg+2].[Br-]>O1CCCC1>[O:25]1[C:26]2[CH:27]=[CH:28][C:29]([C:20]([OH:22])([CH3:21])[CH2:19][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:1])([CH3:23])[CH2:3]3)=[CH:30][C:31]=2[O:32][CH2:24]1
Reactant: CC(=O)CN1CC(C)(C)Cn2c1nc(-c1ccncn1)cc2=O
Reactant: [c-]1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1(C)CN(CC(C)(O)c2ccc3c(c2)OCO3)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of 0.3 g (0.957 mmol) of 7,7-dimethyl-9-(2-oxo-propyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 2 ml of anhydrous tetrahydrofuran at −2° C. was added 2.1 ml (9.57 mmol) of a solution of 3,4-(methylenedioxy)phenylmagnesiumbromide (1M solution in tetrahydrofuran/toluene 50/50) during 20 min. After stirring for 15 min. at room temperature the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with dichloromethane and the extracts washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of ethyl acetate/cyclohexane in the proportions 50/50 to 100/0 to give 0.210 g (50%) of product. Mp.: 194-196° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].[C:35]([O:46][CH3:47])(=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39](O)=[O:40])[CH:37]=1.C(N(CC)CC)C>ClCCl>[CH3:47][O:46][C:35](=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:13][C:14]2[CH:34]=[CH:33][CH:32]=[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:15]=2)=[O:40])[CH:37]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Add ethyldimethylaminopropylcarbodiimide hydrochloride (2.47 g, 12.9 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.54 g, 5.14 mmol) and methyl hydrogen isophthalate (1.11 g, 6.17 mmol) in dichloromethane (40 mL) at 0° C. Add triethylamine (3.59 mL, 25.7 mmol) and stir at room temperature for 72 hours. At 5 hours, add additional methyl hydrogen isophthalate (200 mg). Stir overnight. Wash the mixture twice with 2N hydrochloric acid, saturated sodium bicarbonate, brine, dry, and concentrate. Triturate the residue with 1:1 hexanes: dichloromethane, and filter to afford the title compound as an off-white powder (1.83 g, 77%): 1H NMR (CDCl3) δ 0.97 (t, 3H), 1.59 (sextet, 2H), 2.56 (s, 3H), 2.72 (t, 2H), 3.98 (s, 3H), 5.20 (s, 2H), 6.49 (d, 1H), 7.25 (m, 1H), 7.42 (t, 1H), 7.56-7.64 (m, 3H), 7.79 (s, 1H), 7.89 (s, 1H), 8.15 (d, 1H), 8.24 (d, 1H), 8.48 (s, 1H), 12.75 (s, 1H).