Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.S(OC)(O[CH3:16])(=O)=O.COC1C2C=CC=CC=2SN=1>CC(=O)CC>[CH3:16][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2]1
Reactant: COS(=O)(=O)OC
Reactant: O=c1[nH]sc2ccccc12
Agent: COc1nsc2ccccc12
Agent: [Li]
Solvent: CCC(C)=O
Product: Cn1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 90 h
Yield: 77 %

Procedure:
To a stirred suspension of 1,2-benzisothiazolin-3-one lithium salt (10.0 g, 63.7 mmol) in butanone (30 ml) was added dropwise dimethyl sulfate (8.4 g, 6.4 ml, 66.9 mmol). The resulting slurry was stirred at room temperature for 90 hours. HPLC analysis showed greater than 96% alkylation of 1,2-benzisothiazolin-3-one lithium salt. The solvent was evaporated and the crude product distilled under reduced pressure to give a combined 77% yield of N-methyl-1,2-benzisothiazolin-3-one and 3-methoxy-1,2-benzisothiazole, with N-methyl-1,2-benzisothiazolin-3-one isolated in 94% purity. The ratio of N-alkylated material to O-alkylated material was 90:10.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].FC(F)(F)C(O)=O.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH:30]=O)[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CN(C=O)C>[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[CH2:30][NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)[C@@H](CN[C@H](C(=O)O)[C@@H](C)CC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84 %

Procedure:
Isoleucine (1.31 g, 9.95 mmol) was suspended in anhydrous methanol (10 ml) and trifluoroacetic acid (1.133 g, 0.77 ml, 9.95 mmol) was added. The mixture was stirred until all the isoleucine had dissolved and the solvent was then removed under reduced pressure. Anhydrous DMF (10 ml) was added to the resulting isoleucine trifluoroacetate salt followed by 3 Å molecular sieves and a solution of 2 (1.47 g, 4.9 mmol) in anhydrous DMF (5 ml). After 15 minutes the solution was treated with sodium triacetoxy borohydride (1.58 g, 7.45 mmol) and stirred overnight. The resulting suspension was filtered through celite, diluted with ethyl acetate (50 ml) and washed with saturated sodium chloride solution (2×35 ml). The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield the acid (1.36 g, 84%) as a yellow oil.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:33])[CH:16]=1)[C:9]([O:11]C)=[O:10].CO>C1COCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:33])[CH:16]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cncc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3C(=O)O)cc(=O)oc2c1OC1CCCC1
Reaction time: 3 h

Procedure:
Lithium hydroxide (1 mL, 1M, 1 mmol) was added to a solution of methyl 5-chloro-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)nicotinate, MeOH (0.8 mL), and THF (1.2 mL). The mixture was stirred for 3 h, quenched with 1N HCl (3 mL), and extracted with EtOAc. The organic extract was dried, filtered, concentrated and purified by reverse-phase HPLC (25→100% MeCN/H2O) to give 5-chloro-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)nicotinic acid: 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 7.85 (d, 1H), 7.19 (d, 1H), 4.83 (m, 1H), 4.74 (s, 1H), 3.90 (s, 3H) 1.85-1.54 (m, 8H); MS (ESI): 430.9.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:30](OC)=O)#[N:26]>C1COCC1.O.C(OC(=O)C)C>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[CH:21]=[CH:20][C:7]4[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=4[CH:5]=3)[N:22]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])#[N:26]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Temperature: 75 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (240 mg, 0.785 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil) (23.01 mg, 0.575 mmol) in THF (5 ml) at room temperature (note slight effervescence). The resultant mixture was stirred at room temperature for 30 mins, methyl 3-cyano-4-(methyloxy)benzoate (100 mg, 0.523 mmol) was then added and the reaction mixture was heated to reflux (75° C.) for 45 mins. The reaction mixture was diluted with water and ethylacetate and the layers partitioned, solid was present in the bi-phasic mixture so this was transferred to a conical flask and stirred at room temperature for 2 h at room temperature. The mixture was then partitioned and the organic layer concentrated in vacuo. to yield the title compound (280 mg, 0.502 mmol, 96% yield) as a yellow oil. MS (ES): C25H26N4O4 requires 447; no mass ion present. 1H NMR (400 MHz, CDCl3) δ 1H, d (8.44), 1H, dd (8.38), 2H, m (7.89-7.95), 1H, m (7.35-7.42), 1H, m (7.13-7.17), 3H, s (4.06), 4H, m (3.50-3.66), 4H, m (2.87-3.06), 9H, s (1.50).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:15]1(C)C=CC=CC=1>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:15])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: Cc1ccccc1
Agent: Cl
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
The resulting Grignard reagent was cooled to room temperature and was added dropwise over 20 minutes with 22.1 g (0.1 mol) of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone dissolved in 200 ml of dry toluene. After completion of adding, the reaction liquid was subjected to reaction for 1.5 hours at room temperature and then poured into a solution of 100 ml of conc. hydrochloric acid in 900 ml of ice-water to effect extraction. The resulting organic layer was then washed with 500 ml of 10% aqueous solution of sodium hydroxide and then with 500 ml of water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 17.2 g of a crude product. The crude product was subjected to distillation (boiling point: 60° to 62° C./0.22 mmHg) and then column chromatography (silica gel; hexane:acetone=15:1) for separation and purification to give 4.5 g of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(N(C(C)C)CC)(C)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
To a solution of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.300 g, 1.02 mmol) in of methylene chloride (5 mL) was added diisopropylethyl amine (0.18 mL, 1.0 mmol) followed by 4-morpholine carbonylchloride (0.11 mL, 1.0 mmol). The mixture was stirred at rt for 6 days, and diluted with ethyl acetate. It was then washed twice with water, dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel (50% EtOAc/hexanes) gave the above-named compound (0.080 g, 19.6%) as a white solid: mp 185-186° C. NMR (CDCl3) δ 7.56 (2H, d), 7.44 (2H, d), 7.07 (1H, s), 6.51 (1H, s), 3.79 (4H, m), 3.54 (4H, m).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=3[CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:5][CH2:4][O:3]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([F:77])[CH:72]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:77][C:73]1[CH:72]=[C:71]([N:24]2[CH2:25][CH2:26][CH2:27][CH:23]2[C:11]2[CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=[C:15]3[C:10]=2[O:9][C:8]([N:6]2[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:17][C:16]3=[O:18])[CH:76]=[CH:75][CH:74]=1
Reactant: Fc1cccc(Br)c1
Reactant: COC(=O)c1cc(C2CCCN2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCCN2c2cccc(F)c2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
Diacetoxypalladium (8.44 mg, 0.04 mmol) was added to a stirred mixture of methyl 2-((R)-2-methylmorpholino)-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.35 g, 0.94 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.046 g, 0.08 mmol), 1-bromo-3-fluorobenzene (0.131 ml, 1.17 mmol) and cesium carbonate (0.459 g, 1.41 mmol) suspended in 1,4-dioxane (9 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, the insoluble were removed by filtration and the filtrate concentrated. The crude product was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in EtAc. The solvents were evaporated to dryness to afford methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.279 g, 64%) as a beige foam. Mass Spectrum: m/z [M+H]+=467.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18](O)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1COCC1>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18]([SH:43])=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Oc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: Sc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-ol (257 mg) was dissolved in THF, and Lawesson's reagent (200 mg) was added to the solution, followed by stirring the mixture at 60° C. for 8 hours. Then Lawesson's reagent (110 mg) was further added and the mixture was stirred at 60° C. for 8 hours. Water was added to the mixture and then the mixture was extracted with dichloromethane. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium: sulfate and the residue was purified by (ethanol:ethyl acetate=10:1) to obtain 103 mg of 3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-thiol. Yield: 39%.
Reaction SMILES: [Na].[C:2]1([N:8]2[C:16]3[N:15]=[C:14](Cl)[N:13]4[CH2:18][C@H:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl-].[CH2:30]([OH:33])[CH2:31][CH3:32]>>[C:2]1([N:8]2[C:16]3[N:15]=[C:14]([O:33][CH2:30][CH2:31][CH3:32])[N:13]4[CH2:18][C@H:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: ClC1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CCCOC1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12
Yield: 75 %

Procedure:
Then, 20 mg sodium was reacted in 3 ml -propanol. The solution was cooled with an ice bath and 209 mg of the above product (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-chloro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine was added with stirring. After 1 hour the reaction was poured into 100 ml saturated NaCl solution and extracted with 200 ml CHCl3. The organic layer was dried over MgSO4, filtered and concentrated to yield an oil which was purified by radial chromatography (5-10% MeOH/CHCl3, 2 mm plate) to yield 168 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-propoxy-3H-imidazo-[1,2-c]pyrazolo[4,3-e]pyrimidine (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(Cl)c1

Procedure:
Using 2,4-dichlorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 13. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 3H), 6.93 (s, 1H), 6.83 (s, 1H), 3.78 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.19 (m, 2H), 3.0 (m, 2H), 2.82 (m, 4H), 2.58 (m, 1H), 1.80 (m, 2H) LRMS (ES+): 391 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[CH3:23][OH:24].ClCCl>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([NH2:1])=[O:24])[CH2:19][CH2:18]1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: CN1CCNCC1
Reactant: CO
Agent: O=C(O)C1(c2cccnc2)CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(N)=O)CC1

Procedure:
Prepare by the method of Preparation 16 using 1-benzyl-(4-(pyridin-3-yl)-piperidine-4-carboxylic acid and 4-methylpiperazine to give, after chromatography on silica gel eluting sequentially with 3% methanol/dichloromethane containing 0.5% concentrated aqueous ammonia, 6% methanol/dichloromethane containing 0.5% concentrated aqueous ammonia, 9% methanol/dichloromethane containing 0.5% concentrated aqueous ammonia, and then 12% methanol/dichloromethane containing 0.5% concentrated aqueous ammonia, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br.C(O)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCCCc1ccc(-c2ccc(OC)c(F)c2)nc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1

Procedure:
2-(m-Fluoro-p-methoxyphenyl)-5-heptylpyridine (X) (13 g, 0.043 mol) obtained at the step (III) hydrobromic acid (47%) (50 ml) and acetic acid (140 ml) were heated under reflux for 30 hours, followed by cooling the reaction fluid, pouring it in water, filtering off the resulting crystals, dissolving the crystals in 2N-NaOH aqueous solution (about 100 ml), further adding acetic acid (30 ml) to obtain an acidic solution filtering off deposited crystals and recrystallizing them from ethyl alcohol to obtain 2-(m-fluoro-p-hydroxyphenyl)-5-heptylpyridine (a compound of the formula (XI) wherein X=f and R1 =C7H15) (7.2 g) having a m.p. of 83.7°-86.1° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH3:19])[C:7]=1[CH:20]=[O:21])[CH2:2][CH2:3][CH3:4].O1CCC[CH2:23]1.O1CCCC1.C[Mg]Br>O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH3:19])[C:7]=1[CH:20]([OH:21])[CH3:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C=O)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Product: CCCCOc1c(C(C)O)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of 4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinealdehyde (0.98 g, 24 mmol) in tetrahydrofuran (20 mmol) was added 3N methylmagnesium bromide tetrahydrofuran solution (1.5 ml, 4.5 mmol) at 0° C. and the obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 4-butoxy-6,7-dichloro-3-(1-hydroxyethyl)-2-methyl-1(2H)-isoquinolinone (0.95 g, 92.2%) as crystals.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH2:10][C:11](=[O:22])[NH:12][C:13]2[S:14][C:15]3[CH2:16][CH2:17][CH2:18][NH:19][C:20]=3[N:21]=2)[CH2:7][C@@H:6]1[NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>>[CH:34]1([CH2:33][CH:18]2[CH2:17][CH2:16][C:15]3[S:14][C:13]([NH:12][C:11]([CH2:10][N:8]4[CH2:9][C@H:5]([O:4][CH3:3])[C@@H:6]([NH:23][C:24]([C:26]5[S:27][C:28]([Cl:31])=[CH:29][CH:30]=5)=[O:25])[CH2:7]4)=[O:22])=[N:21][C:20]=3[NH:19]2)[CH2:36][CH2:35]1
Reactant: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCCN3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: BrCC1CC1
Agent: Cl
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(CC2CC2)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 94.3 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide dihydrochloride (example 94.2) was reacted with 1-(bromomethyl)cyclopropane to give 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-1-[(5-cyclopropylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-4-methoxy-pyrrolidin-3-yl}-amide. Yellow solid. MS 510.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[C:12]([C:17]1[CH2:18][S:19][CH2:20][CH2:21][N:22]=1)(OCC)=[O:13].CCCCCC>CCOCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:17]3=[CH:18][S:19][CH2:20][CH2:21][N:22]3[C:9]2=[O:10])=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)C1=NCCSC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C1C2=CSCCN2C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 8.6 g of 4-chloro-2-fluorophenylisocyanate in 20 ml of anhydrous ether was added dropwise to a mixture of 9.8 g of crude 3-carbethoxy-5,6-dihydro-1,4-thiazine and 10 drops of triethylamine in 20 ml of ether. After the addition, 30 ml of hexane was added dropwise in 20 min. The solution was stirred at room temperature for 3 hrs. The solution was concentrated in vacuo to remove solvent. The resulting oil was crystallized from ether to give 10 g of 2-(4-chloro-2-fluorophenyl)-5,6-dihydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione, m.p. 117.5°-120.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH:9]=[CH:8][C:7]1=[O:18])=[O:5])[CH3:2].BrBr.C(Cl)Cl.O>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:18])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1C(=O)C=CCC1c1ccccc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)cccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 21 h
Yield: 29.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 24.4 grams (0.100 mole) of crude 2-ethoxycarbonyl-3-phenylcyclohex-5-enone in 50 mL of carbon tetrachloride was cooled in an ice bath, and a solution of 16.1 grams (0.100 mole) of bromine in 50mL of acetic acid was added dropwise. Upon completion of addition, the reaction mixture was stirred at the ice-bath temperature for 30 minutes. After this time the reaction mixture was warmed to reflux where it was stirred for about 21 hours. The reaction mixture was cooled and then was stirred with 80 mL of methylene chloride and 80 mL of water. The layers were separated, and the organic layer was washed with two portions of water and with one portion of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and magnesium sulfate and then was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 2:1-heptane and methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 7.1 grams of ethyl 6-phenylsalicylate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1O)(=[O:3])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1[F:27])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(F)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
(2,3,4-Tri-O-acetyl)-L-fucopyranose (13.1 g) is dissolved in methylene chloride (100 ml), and thereto is added with stirring DAST (10.9 g) under ice-cooling, and the mixture is stirred for 4 hours under ice-cooling. The reaction mixture is poured into ice-water (200 g), and the mixture is separated. The organic layer is dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:4→1:2) to give (2,3,4-tri-O-acetyl)-L-fucopyranosyl fluoride (10.6 g) in the form of a mixture of α-anomer and β-anomer.