Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:26])([CH3:25])[C:5]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:23]O)[CH3:22])=[CH:17][CH:16]=1)([OH:12])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[Cl:27][C:28]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Cl.O>CS(C)=O.C(O)(=O)C>[Cl:27][C:28]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:23]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:5]([OH:12])([C:4]([CH3:26])([CH3:25])[CH3:3])[CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:16][CH:17]=1)[CH3:22]
Reactant: CC(=NO)c1ccc(OCC(O)(Cn2cncn2)C(C)(C)C)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(=NCc1ccc(Cl)cc1Cl)c1ccc(OCC(O)(Cn2cncn2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
1.44 g (0.06 mol) of sodium hydride (30% strength in paraffin oil) are added to a solution of 14.94 g (0.045 mol) of 3,3-dimethyl-2-[4-(1-hydroximinoethyl)-phenoxymethyl]-1-(1,2,4-triazol-1-yl)-2-butanol (Example 2) in 120 ml of absolute dimethylsulphoxide. The reaction mixture is stirred at room temperature for about 1 hour, until a clear solution has formed. 3.33 ml (0.06 mol) of 2,4-dichlorobenzyl chloride are then added and the reaction mixture is subsequently stirred at room temperature for 1.5 hours. Thereafter, water and glacial acetic acid are carefully added and the mixture is concentrated. The residue is taken up in ethyl acetate and the mixture is washed several times with dilute sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed over a silica gel column (methylene chloride/ethyl acetate=4:1) and the product is recrystallized from acetonitrile. 16.2 g (73% of theory) of 2-{4-[1-(2,4-dichlorobenzylimino)-ethyl]-phenoxymethyl} -3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 101° C. are obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCCC1)([O:16][C:17](C)(C)[CH3:18])=O.CN1C[C@@H]2[C@H]3N(C[C@@H](C2)C1)CCCC3>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][OH:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: CN1C[C@@H]2C[C@H](C1)[C@@H]1CCCCN1C2
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO

Procedure:
This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-piperidine is used insead of 1-Boc-pyrrolidine, and (+)-sparteine surrogate is used instead of (−)-sparteine.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=O)[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CC(C)([O-])C.[Na+].C(Br)C.Cl>O1CCCC1>[Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 35 °C
Reaction time: 144 h
Yield: 110.1 %

Procedure:
To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5 g, 21.13 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06 g, 42.3 mmol) was added (causing a temperature rise from 22° C. to 27.6° C.), followed by ethyl bromide (6.26 mL, 85 mmol). The reaction was stirred at 35° C. for 144 h at which point only 3.2% (AUC) starting material remained. The reaction mixture was concentrated to give a brown residue, which was dissolved in 1 N hydrochloric acid (106 mL, 106 mmol) and heated at 80° C. for 24 hours, at which point HPLC analysis indicated that the starting material had been consumed. The reaction was cooled to 20° C. and basified with sodium hydroxide (50 wt % in water) to pH>9. The resulting suspension was stirred at 20° C. for 1 hour and filtered. The filter cake was rinsed with water (25 mL) to afford a brown solid (5.18 g). The resulting crude product was dissolved in ethyl acetate and passed through a silica gel plug (50 g) using ethyl acetate (500 mL) as eluent. The filtrate was concentrated to dryness to afford a white solid (3.8 g, 80%).
Reaction SMILES: S1C[CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:8](OC)(OC)OC.[CH3:15][S:16]([OH:19])(=O)=[O:17]>CO.C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:8][O:7][C:4]1[CH2:5][CH2:15][S:16](=[O:19])(=[O:17])[CH2:2][CH:3]=1
Reactant: COC(OC)OC
Reactant: CS(=O)(=O)O
Reactant: O=C1CCSCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COC1=CCS(=O)(=O)CC1

Procedure:
4-Methoxy-1,1-dioxo-5,6-dihydro-(2H)-Thiopyran is prepared from the available tetrahydrothiopyran-4-one (Aldrich) by ketalization with trimethyl orthoformate in methanol containing catalytic sulfuric acid, followed by oxidation with excess m-chlorolperbenzoic acid in methylene chloride, followed by acid promoted elimination of methanol using, for instance, methanesulfonic acid in hot chloroform (to drive off by-product methanol by distillation).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([NH:33][C:34]1[N:35]=[CH:36][C:37]2[N:42]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:41][CH:40]([CH:50]3[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]3)[C:38]=2[N:39]=1)[CH2:30][CH2:31][CH3:32]>CO.[Pd]>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C@@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([NH:33][C:34]1[N:35]=[CH:36][C:37]2[N:42]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH:41]=[C:40]([C@H:50]3[CH2:51][CH2:52][C@H:53]([OH:56])[CH2:54][CH2:55]3)[C:38]=2[N:39]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCNc1ncc2c(n1)C(C1CCC(O)CC1)CN2c1ccc(F)cc1
Agent: [Pd]
Agent: CCCCNc1ncc2c(n1)c([C@H]1CC[C@H](O)CC1)cn2-c1ccc(F)cc1
Agent: CCCCNc1ncc2c(n1)c([C@H]1CC[C@H](O)CC1)cn2-c1ccc(F)cc1
Solvent: CO
Product: CCCCNc1ncc2c(n1)c([C@H]1CC[C@@H](O)CC1)cn2-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of mixture of trans-4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol and 4-(2-(butylamino)-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol (0.035 g, 0.091 mmol) in 5 mL MeOH was added Pd/C (0.004 g, 10 wt %). The mixture was stirred overnight under air. After filter through a plug of celite, the filtrate was concentrated and purified by ISCO to provide cis-4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol (0.010 g, 13% over 3 steps) and trans-4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol (0.012 g+0.040 g, 52% over 3 steps). Cis-isomer (UNC1861A): 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.55-7.49 (m, 3H), 7.32-7.25 (m, 2H), 4.06-3.99 (m, 1H), 3.43 (t, J=7.1 Hz, 2H), 2.97 (tt, J=10.6, 3.7 Hz, 1H), 2.06-1.96 (m, 2H), 1.93-1.82 (m, 4H), 1.79-1.68 (m, 2H), 1.68-1.59 (m, 2H), 1.49-1.39 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); MS m/z 383.3 [M+H]+. Trans-isomer (UNC1860A): 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.53-7.47 (m, 3H), 7.28 (t, J=8.7 Hz, 2H), 3.69-3.57 (m, 1H), 3.42 (t, J=7.1 Hz, 2H), 2.83 (tt, J=12.4, 3.2 Hz 1H), 2.20-2.13 (m, 2H), 2.11-2.02 (m, 2H), 1.73-1.58 (m, 4H), 1.53-1.39 (m, 4H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 383.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C:20]([O-])(=[O:22])[CH3:21].[Na+].C(OC(=O)C)(=[O:27])C>N.N1C=CC=CC=1>[C:20]([NH:19][C:16]1[C:17]2[NH:18][C:2](=[O:27])[N:3]([C:12]=2[N:13]=[CH:14][N:15]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ncnc2c1[nH]c(=O)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 120 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
8-Bromo-2′-deoxyadenosine (4.2 g, 12.5 mmol) prepared in above was dissolved in 80% acetic acid-acetic anhydride (1:1, v/v, 250 mL), and sodium acetate (18.5 g, 225 mmol) was added thereto. The mixture was stirred at 120° C. for 3 hours and then extracted with ethyl acetate-water (500 mL/500 mL). The organic layers were combined, and the solvent was removed under reduced pressure. The obtained crude product was dissolved in 28% aqueous ammonia-pyridine (1:1, v/v, 250 mL). The solution was stirred at room temperature for 5 hours. Then, the reaction solvent was evaporated under reduced pressure. The resulting solid was sufficiently washed with ethanol and filtered to give 2′-deoxy-7,8-dihydro-6-N-acetyladenosin-8-one (1.9 g, yield: 55%).
Reaction SMILES: Cl[C:2]1[CH:10]=CC(S(C)(=O)=O)=C[C:3]=1C(O)=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([OH:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].IC(C)C>O>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH:2]([CH3:10])[CH3:3])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: O
Solvent: CC(C)I
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 42 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 2-iodopropane in 20 ml water and obtained in 42% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:29])[C:7]([CH3:28])([CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:25][OH:26])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:26][CH2:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:28])([CH3:27])[C:6]([OH:29])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(CO)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(CO)CCCCC(C)(C)C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a homogeneous solution of potassium hydroxide (1.18 g, 21 mmol) in water (1.12 mL) and ethanol (3.8 mL) was added 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (2.9 g, 7.5 mmol) and the reaction mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo, cooled to room temperature, and the residue was extracted with diethyl ether (2×50 mL). The pH of the aqueous layer was adjusted to 1 by addition of hydrochloric acid. The product was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude product which was purified by column chromatography on silica (hexanes:ethyl acetate=60:40) to yield 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid (2.0 g, 81%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.64 (br., 3 H), 3.50 (d, 2 H, J=4.4 Hz), 1.60-1.20 (m, 17 H), 1.16 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 65.2, 42.1, 40.5, 40.1, 30.6, 27.1, 25.2, 25.0. HRMS (LSIMS, nba): Calcd. for C18H35O5 (MH+): 331.2484, found 331.2484.
Reaction SMILES: N(C1C=C(C2SC(C(NCC([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])(NS(C3C(C)=CC(C)=CC=3C)(=O)=O)C(N)=O)=O)=CC=2)C=CC=1)C(N)=N.N.N(C1C=C(C2SC(C([NH:61][CH2:62][C:63](CCO)([NH:67][S:68]([C:71]3[C:76]([CH3:77])=[CH:75][C:74]([CH3:78])=[CH:73][C:72]=3[CH3:79])(=[O:70])=[O:69])[C:64]([NH2:66])=[O:65])=O)=CC=2)C=CC=1)C(N)=N>>[NH2:61][CH2:62][CH:63]([NH:67][S:68]([C:71]1[C:72]([CH3:79])=[CH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77])(=[O:69])=[O:70])[C:64]([NH:66][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])=[O:65]
Reactant: CC(=O)OCCC(CNC(=O)c1ccc(-c2cccc(NC(=N)N)c2)s1)(NS(=O)(=O)c1c(C)cc(C)cc1C)C(N)=O
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CCO)(CNC(=O)c2ccc(-c3cccc(NC(=N)N)c3)s2)C(N)=O)c(C)c1
Agent: N
Product: CC(=O)OCCNC(=O)C(CN)NS(=O)(=O)c1c(C)cc(C)cc1C

Procedure:
3-{[5-(3-Guanidino-phenyl)-thiophene-2-carbonyl]-amino}-2-(2,4,6-trimethyl-benzenesulfonylamino)-2-acetoxyethyl propionamide (X-9) was treated with excess methanolic ammonia resulting in the formation of 3-{[5-(3-Guanidino-phenyl)-thiophene-2-carbonyl]-amino}-2-(2,4,6-trimethyl-benzenesulfonylamino)-2-hydroxyethyl propionamide (X-9).
Reaction SMILES: C([N:3](CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N-]=[N+]=[N-].[Na+].[CH2:18](O)[C:19]1C=C[CH:22]=[CH:21][CH:20]=1>CC(C)=O.O.C1C=CC=CC=1>[C:9](=[O:10])([O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:3]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 144.7 %

Procedure:
To a solution of carboxylic acid 20 (1.88 g, 9.58 mmol) and triethylamine (1.65 mL, 1.26 g, 12.5 mmol) in acetone (30 mL) at 0° C. was added ethyl chloroformate (0.92 mL, 1.0 g, 9.6 mmol) dropwise over several minutes. After the addition was complete the solution was stirred for 1 hour at 0° C. A solution of sodium azide (1.87 g, 28.7 mmol) in water (30 mL) was added and the reaction mixture was stirred for an additional hour at 0° C. The solution was poured into ice water and the resulting mixture was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed sequentially with sodium bicarbonate and brine and then dried over sodium sulfate. Concentration gave a residue which was dissolved in dry benzene (50 mL) and heated under reflux for 1.5 hours. Benzyl alcohol (2.07 g, 19 mmol) was added and heating under reflux was continued for an additional 2.5 hours. Concentration gave a pale yellow oil which was crystallized from Et2 O/hexane to give the title compound 21 (2.1 g, 73%) as colorless crystals: mp 73°-76° C.
Reaction SMILES: [CH2:1]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:17]([N:25]1[CH2:30][CH2:29][CH2:28][C:27]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=2)([CH2:31][CH2:32][CH2:33]N2CCC(C(N3CCCC3)=O)CC2)[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[OH2:24].[ClH:53].[C:17]([N:25]1[CH2:30][CH2:29][CH2:28][C:27]([CH2:31][CH2:32][CH2:33][N:11]2[CH2:10][CH2:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]#[N:15])[CH2:13][CH2:12]2)([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=2)[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: N#CC1(Cc2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Product: O
Yield: 105.6 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 4, starting from 2.5 g of 4-benzyl-4-cyanopiperidine, 5 g of the compound obtained in step B of EXAMPLE 1, 3.7 g of K2CO3 and 50 ml of DMF. The product obtained is chromatographed on silica H using DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum to give 2.8 g of the expected product after crystallization from iso ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][OH:14])[C:6]=2[CH:23]=1.[CH:24](OC(=O)C)=[O:25]>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:7]1[C:6]2[CH:23]=[C:2]([NH:1][CH:24]=[O:25])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1)=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(N)cc12
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(NC=O)cc12

Procedure:
To a solution of 0.59 g of 5-amino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 12 ml of methylene chloride is added 0.17 g of acetic formic anhydride at 5°-10° C., and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from n-hexane, after which the crystals are collected by filtration, to obtain 0.52 g of colorless, crystalline 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-formylamino-1,2-benzoisoxazole having a melting point of 104°-105° C.
Reaction SMILES: [CH3:1][Mg]Br.Cl[C:5]1[C:6](=[O:12])[NH:7][N:8]=[CH:9][C:10]=1[Cl:11]>CCOCC>[CH3:1][C:5]1[C:6](=[O:12])[NH:7][N:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C[Mg]Br
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: CCOCC
Product: Cc1c(Cl)cn[nH]c1=O
Reaction time: 3 h

Procedure:
Into a 500 ml flask, 189 g of methylmagnesium bromide (1 mol/liter of an ether solution) was charged, and 10.0 g of 4,5-dichloro-3(2H)pyridazinone was gradually added thereto at a temperature of about 15° C. The mixture was stirred at a temperature of from 40° to 50° C. for about 3 hours. The disappearance of the starting dichloropyridazinone was confirmed by thin layer chromatography (developer; ethyl acetate:acetone =2:1, v/v), whereupon the reaction was terminated. The reaction solution was transferred to a separating funnel, and about 300 ml of a saturated sodium chloride aqueous solution was added thereto, and then the mixture was vigorously shaken. The aqueous layer was removed. The organic layer was washed with about 200 ml of water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The brown crystals thereby obtained were recrystallized from ethyl acetate to obtain 4.54 g of the above identified compound having a melting point of from 132° to 134° C. as colorless crystals.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>[N+](C)([O-])=O>[N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
In step c, the t-butyl ester functionality of (12) is hydrolyzed, with for example, HCl in nitromethane, to give the corresponding, 6-(morpholine-4-carbonyl)nicotinic acid (13).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[Mg+2].[Cl-].[Cl-]>C(#N)C.CCOC(C)=O>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carboxylic acid (3.749 g, 13.7 mmol) and thionyl chloride (9.97 mL, 137 mmol) was heated at reflux. After 2 hours, the reaction was cooled to 23° C. and concentrated in vacuo, azeotroped with toluene (2×20 mL) and further dried on the vacuum line for 90 minutes. A solution of diethyl malonate (2.17 mL, 14.4 mmol) in ACN (50 mL) in an oven-dried round-bottomed flask, was cooled to 0° C. and treated with MgCl2 (1.30 g, 13.7 mmol), followed by TEA (3.99 mL, 28.7 mmol). The reaction was warmed to 23° C. After 2 hours and 30 minutes, a solution of the crude acid chloride in ACN (10 mL) was added, and the reaction was heated to 50° C. After 15 hours, the reaction was cooled to 23° C., diluted with EtOAc (400 mL), and washed with a 10% HCl solution (300 mL). The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, and concentrated in vacuo affording 5.50 g of diethyl 2-(4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate. MS m/e=417.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CN(C)C=O.Br[CH2:34][F:35]>O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:34][F:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Reactant: FCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc(C)cc2)cc1OC
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Two hundred milligrams (200 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (0.586 mmol), 28 mg (0.70 mmol) of 60% sodium hydride, 2 ml of anhydrous N,N-dimethylformamide and 1 ml of anhydrous diethyl ether were mixed and 0.5 ml of bromofluoromethane was added thereto at −5° C. The mixture was stirred at −5° C. for 30 minutes and then stirred at 0° C. for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=2:1) to give 205 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(4-methylphenyl)acrylamide (the present compound 1-4).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Br
Yield: 57 %

Procedure:
This reaction was carried out similarly to Example 1, with 2-bromo-5-nitrobenzaldehyde and malonic acid in pyridine and with piperidine. The product of melting point 185° C, was obtained in 57% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH3:25])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CI
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1cccc(-c2csc3cnc(Cl)nc23)c1)S(C)(=O)=O
Yield: 93.4 %

Procedure:
N-(3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (200 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and sodium hydride (36 mg, 0.89 mmol) was slowly added at 0° C. 10 minutes later, after adding iodomethane (100 mg, 0.71 mmol), the reaction mixture was stirred for an hour, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered, and then concentrated. The target compound (195 mg, 94% yield) was obtained without purification.