Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:28](C1CC(=O)N(O)C1=O)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29].CN(C=O)C>ClCCl>[CH3:6][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:28]([O:30][CH2:31][CH:32]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]3[C:44]2=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:29])=[CH:15][CH:16]=1)=[O:2])[CH3:7]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Reaction time: 10 h

Procedure:
Boc-para-aminophenylalanine (2.6 mmol; 0.72 g) was dissolved in 12 ml of dichloromethane (DCM) (from Dow Chemical, Midland, Mich.) containing 3.85 mmol of triethylamine (TEA) (from Aldrich, Milwaukee, Wis.; distilled before use). 1.3 Grams (3.85 mmol) of Fmoc-N-hydroxysuccinimide was added and the solution was left at room temperature for 10 hours. The solution was evaporated to dryness in vacuo. The residue was dissolved in 100 ml ethyl acetate and washed with 50 ml of 5% NaHCO3. The solution was filtered and the NaHCO3 wash was repeated two more times. The precipitate from the three NaHCO3 washes was then extracted with a mixture of three parts (v/v) ethyl acetate to one part saturated KHSO4. The organic layer was isolated and concentrated in vacuo. After removal of most of the ethyl acetate by vacuum the product was precipitated with petroleum ether. The product was recrystallized twice using an ethyl acetate-petroleum ether mixture to yield 0.83 g (64%) with a melting point of 118-120° C. Thin layer chromatography was performed according to well-known procedures and displayed a spot with Rf=0.28. [α]D21 =-6.29 (c1.7, DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:11][N:10]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+].[Cl:31][C:32]([Cl:36])=[CH:33]CCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:28][CH2:25][CH:33]=[C:32]([Cl:36])[Cl:31])=[CH:4][CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][C:9]1[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:11][N:10]=1
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2C(F)(F)F)c(Cl)c1
Reactant: ClCC=C(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)ccc(OCC=C(Cl)Cl)c2Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a mixture of 0.56 g, of 3,5-dichloro-4-(3,5-bistrifluoromethyl-2-pyridyloxy)phenol, 0.22 g of potassium carbonate and 20 ml of N,N-dimethylformamide, a solution prepared by dissolving 0.23 g of 1,1,3-trichloro-1-propene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 7 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.50 g of 3,5-dichloro-4-(3,5-bistrifluoromethyl-2-pyridyloxy)-2-(3,3-dichloro-2-propenyloxy)benzene, yield 70%; m.p., 78.2° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C3(C)CCOCC3)cc2)cn1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: N[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]([O-])=O.[Na+].C1C(C(O)=O)=CC=C(N)C=1.C(O)(=O)C1C=CC=CC=1.C=CC1C=CC=CC=1>C(O)C.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: NC=Cc1ccccc1
Reactant: O=N[O-]
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Solvent: C=Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(N)cc1

Procedure:
The diazonium salt of 4-aminostyrene is prepared as above from 3.6 g aminostyrene, 2.1 g sodium nitrite, and 150 g water. Ethanol, 10 g, is added to completely dissolve the diazonium salt. A solution of PABA-treated MMC is added to the diazonium salt solution, and it is allowed to react for 18 hours under mixing. The solution is filtered to provide MMC solution at about 11 wt %. This MMC contains both benzoic acid and styrene functionalities covalently attached to the MMC particle.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.CO.O>[C:1]1([CH:7]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CN1CCCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 2-(3-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetate (0.5 g, 1.23 mmol) in THF/MeOH/water (12 mL, 7:3:2) at 5° C. was added LiOH.H2O (0.15 g, 3.7 mmol). After stirring at rt for 4 h, the solvent was removed under vacuum. The residue was diluted with water and the pH was adjusted to 4 with diluted HCl, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in ethyl acetate and crashed out of pentane at cool condition to afford pure 2-(3-(phenyl(4-(trifluoromethyl)-phenyl)methyl)piperidin-1-yl)acetic acid (0.3 g, 65% yield) as an off white solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([CH3:24])[CH2:19]2)=[CH:16][C:15]2[C:11](=[CH:12][N:13](C3CCCCO3)[N:14]=2)[CH:10]=1.CO.CS(O)(=O)=O.C(Cl)Cl>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][O:21][CH:20]([CH3:24])[CH2:19]1)[NH:14][N:13]=[CH:12]2
Reactant: CC1CN(c2cc3nn(C4CCCCO4)cc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC1CN(c2cc3[nH]ncc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Temperature: 40 °C
Yield: 69.7 %

Procedure:
To a round bottom flask is added N-(3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (66 mg, 102.86 μmol) and MeOH (5 mL, 123.54 mmol). To the resulting mixture is added MeSO3H (20.229 μL, 308.57 μmol) and the reaction mixture is heated to 40° C. for 6 hours. The reaction mixture is concentrated and dissolved in DCM (100 mL). The solution is washed with a mixture of saturated aqueous sodium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (1×20 mL). The organic solution is extracted with DCM (1×25 mL) and dried over Na2SO4, filtered and concentrated. The residue is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 70%(A):30%(B) over 60 min to give a light yellow solid as the desired product (40 mg, 62% yield). MS (m/z): 557.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[ClH:1].[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([OH:30])=[CH:24][C:23]=1[NH:22][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Product: Cl
Product: Oc1ccc(Cl)c(Nc2ncnc3sc4c(c23)CCNC4)c1

Procedure:
The title compound was prepared in analogy to Example 65A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (2.16 g, 6.63 mmol) and 3-amino-4-chlorophenol (1.00 g, 6.97 mmol) to yield 2.26 g (87%).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][S:15]SC.Cl>CCCCCC.O1CCCC1>[C:6]1([S:12][CH2:13][S:15][CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSSC
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSCSc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
120 ml. of a 1.3M n-butyllithium solution in n-hexane were added dropwise to a solution of 18.8 ml. of thioanisole in 240 ml. of tetrahydrofuran at -20° C. and the reaction mixture was stirred at that temperature for 2 hours. After cooling to -70° C., 16.4 g. of dimethyldisulphide were added to the reaction mixture, which was then stirred at -70° C. for 15 minutes and at room temperature for 1 hour. The reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water and an aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by distillation in vacuo to give 18.0 g. of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:44]1[CH:48]=[CH:47][CH:46]=[C:45]1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:45]4[O:44][CH:48]=[CH:47][CH:46]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccco1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3c2ccco2)cc1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-furaldehyde (0.2 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 20 hours. To the reaction solution were added 2-furaldehyde (0.2 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-furyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 91) (150.0 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=O)[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]2O)[CH:3]=1.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(OCC)C>CN(C=O)C.CO.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:8](=[O:9])[N:7]=[C:5]2[N:4]([C@@H:10]3[O:14][C@H:13]([CH2:15][OH:16])[C@H:12]([O:17]2)[CH2:11]3)[CH:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO
Temperature: 150 °C
Yield: 101.4 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar, reflux condensor, and nitrogen inlet was charged with 5 g of ribothymidine, 4.7 g (1.2 eq) of diphenyl carbonate and 150 mg of sodium bicarbonate in 10 mL of DMF. The mixture was heated to 150° C. for 35 minutes. The black solution was diluted with 10 mL of MeOH and slowly added to 200 mL of diethyl ether. The tan product was filtered and dried to yield 4.4 g (96%) of anhydrothymidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[S:36][C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[S:36][C:32]([CH3:31])=[CH:33][N:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.093 g, 0.6 mmol, 1.2 eq), EDCI.HCl (0.103 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.5 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the mixture was stirred at room temperature for 18 h. The mixture was then added with water, and the organic layer was separated and washed with water, and the product was purified by preparative TLC. Yield: 25 mg (15%). 1H NMR (400 MHz, DMSO-d6): δ 1.34-1.37 (m, 2H), 1.50-1.53 (m, 2H), 2.31 (s, 3H), 2.35 (s, 3H), 2.83-2.84 (d, J=4.8 Hz, 3H), 7.27 (d, J=1.2 Hz, 1H), 7.39-7.47 (m, 4H), 7.60 (d, J=1.6 Hz, 1H), 7.76-7.78 (d, J=8.4 Hz 1H), 7.83-7.85 (m, 2H), 8.02 (m, 2H), 8.45 (m, 1H), 9.51 (s, 1H) LCMS: (ES+) m/z=540 (M+H)+
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=1)[CH:2]=[CH2:3].[OH2:15].C[N+]1([O-])CC[O:20]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.[Os](=O)(=O)(=O)=O>[OH:15][CH:2]([CH2:3][OH:20])[CH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=1
Reactant: C=CCc1ccnc(C(=O)OCC)c1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC(O)CO)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a mixed solution of ethyl 4-allylpyridin-2-carboxylate (0.28 g) prepared in (1) in acetonitrile (9.0 mL)/water (3.0 mL) were added 4-methylmorpholine N-oxide (0.34 g) and aqueous 4% osmium tetraoxide (0.40 mL). The reaction mixture was stirred at RT for 12 hr. An excess amount of saturated aqueous Na2S2O3 was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: ethyl acetate/methanol=10/1) to give the title compound (0.25 g, 77%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:6].[NH2:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([NH:22][CH2:23][CH:24]2[O:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[O:21])=[C:15]([O:30][CH3:31])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:1].[NH2:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([NH:22][CH2:23][CH:24]2[O:29][CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:6])[CH2:25]2)=[O:21])=[C:15]([O:30][CH3:31])[CH:14]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CNCCO1
Reactant: CCN(CC)C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCN1CCOC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Product: Cl
Temperature: 70 °C
Reaction time: 48 h
Yield: 29.9 %

Procedure:
A mixture of 4-chloro-N,N-diethylbutanamide (2.16 g), 4-amino-5-chloro-2-methoxy-N-(2-morpholinylmethyl)benzenamide (3 g), prepared following the procedure as described in EP-A-0,243,959, and sodium carbonate (1.58 g) in N,N-dimethyl-formamide (90 ml) was stirred for 48 hours at 70° C. The solvent was evaporated and water was added to the residue. This mixture was extracted twice with dichloromethane and the combined extracts were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 95/5). The first fraction was collected and the solvent was evaporated. The residue was converted into the hydrochloric salt in 2-propanol and diisopropyl ether. The salt was filtered off and crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 1.43 g (30.4%) of (±)-2-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-N,N-diethyl4-morpholine-butanamide monohydrochloride. hemihydrate (compound 1; mp. 122.2° C.).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][NH:23]3)=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:43]1[CH:47]=[CH:46]N=[CH:44]1)=[O:42].CN(C=O)C>CCOC(C)=O>[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:23]1[C:24]2[C:19](=[CH:18][CH:17]=[C:16]([C:14]3[S:15][C:11]([CH2:10][CH2:9][CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:12]([C:26]([OH:28])=[O:27])[N:13]=3)[CH:25]=2)[CH2:20][CH2:21][CH2:22]1)=[O:42].[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:43]1[C:44]2[C:19](=[CH:18][CH:17]=[C:16]([C:14]3[S:15][C:11]([CH2:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:13]=3)[CH:25]=2)[CH2:20][CH2:46][CH2:47]1)=[O:42]
Reactant: O=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)NCCC3)sc1CCCOc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (24) was prepared by the following procedure: To ethyl 5-(3-phenoxypropyl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylate (24A) (18 mg, 0.0.42 mmol) and N-(benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (1M) (10 mg, 0.042 mmol) was added DMF (2 mL) and stirred at rt overnight. The reaction mixture was diluted with EtOAc, washed sequentially with NaHCO3, water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylate. LC/MS (APCI): m/z 599.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[CH3:13]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:21][CH:22]=1)[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (MATRIX SCIENTIFIC) (10.7 g, 48.7 mmol) and 4-aminophenylacetic acid ethyl ester (8.7 g, 48.7 mmol) in NMP (50 mL) is stirred for 48 h at 110° C. The reaction mixture is allowed to cool at rt, diluted with EtOAc and H2O. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed brine, dried (Na2SO4), filtered and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 4:1) of the crude product affords the title compound as an orange oil: ES-MS: 380.9 [M+2]+; single peak at tR=5.75 min (System 1); Rf=0.27 (Hexane/EtOAc, 4:1).
Reaction SMILES: O.O.O.O.O.O.O.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+].Br[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O1CCOCC1.O>[O:18]1[CH2:19][CH2:20][CH:16]([CH2:15][S:8]([O-:11])(=[O:10])=[O:9])[CH2:17]1.[Na+:12]
Reactant: BrCC1CCOC1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)([O-])CC1CCOC1
Reaction time: 18 h
Yield: 57 %

Procedure:
Sodium sulfite heptahydrate (6.10 g) was added to a solution of 3-(bromomethyl)tetrahydrofuran (2.0 g) [see Preparation 9] in 1,4-dioxane (9 ml) and water (9 ml). The reaction mixture was then heated under reflux and stirred for 18 hours, cooled and the solvent removed under reduced pressure. The resulting solid was dissolved in water and concentrated to a low volume. The solid formed was then collected to afford sodium tetrahydrofuran-3-ylmethanesulfonate (1.30 g) as a white solid.