Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=O)=O.O>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: COCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)-methyl)piperidine-1-carboxylate (162 mg, 0.557 mmol) and 60% NaH in mineral oil (112 mg, 5 equiv.). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (6 mL) was added slowly. After 5 min, the reaction mixture was allowed to warn to rt slowly. A solution of 3-methoxypropyl methanesulfonate (468 mg, 4 equiv.) in anhydrous THF (5 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to 0° C. and water was added dropwise. After separation, the aqueous layer was extracted with ether (3×). The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3 and brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carboxylate (196 mg, 97% yield) as a clear oil. LC-MS (3 min) tR=2.19 min, m/z 386 (M+Na).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[CH3:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[CH3:33][O:32][C:30]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([S:11][CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]34)[CH:10]=2)=[C:26]([CH3:25])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Reactant: COc1ccc(B(O)O)c(C)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCS3)c(C)c1
Yield: 54.6 %

Procedure:
The tert-butyl(6bR,10aS)-5-(4-methoxy-2-methylphenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (420 mg, 55%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (700 mg, 1.70 mmol) with 2-methyl-4-methoxyphenyl boronic acid (424 mg, 2.55 mmol) using the procedure described in Example 450 Step A.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[CH:25]=O>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)[CH:8]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and benzofuran-2-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, 1H), 7.42 (d, 1H), 7.25-7.14 (m, 5H), 7.07 (d, 1H), 6.55 (d, 1H), 3.91 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.60 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1cnccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cnccc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 4-chloropyridine-3-carbaldehyde (33.44 g), (4-fluorophenyl)boronic acid (39.1 g), tetrakis(triphenylphosphine)palladium (6.73 g), 2 M aqueous potassium carbonate solution (314.4 mL) and 1,2-dimethoxyethane (500 mL) was heated under reflux for 6 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereof, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.04 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:26]1[O:27][C:19]2[CH:18]=[CH:17][C:22]([C@@H:23]3[C:8]4[NH:9][C:10]5[C:15]([C:7]=4[CH2:6][C@H:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]3)=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:21][C:20]=2[O:25]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Reaction time: 96 h
Yield: 36.8 %

Procedure:
To a stirred solution of D-tryptophan methyl ester (11 g) and piperonal (7.9 g) in anhydrous CH2Cl2 (400 mL) cooled at 0° C. was added dropwise trifluoroacetic acid (7.7 mL) and the solution was allowed to react at ambient temperature. After 4 days, the yellow solution was diluted with CH2Cl2 (200 mL) and washed with a saturated aqueous solution of NaHCO3, then with water (3×200 mL) and dried over Na2SO4. The organic layer was evaporated under reduced pressure and the residue containing the two geometric isomers was purified by flash chromatography eluting with dichloromethane/ethyl acetate (97/3) to give as the first eluting product the title compound (6.5 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH2:16])[CH:15]=1.O.Cl>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:16][C:1](=[O:3])[CH3:2])[CH:15]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Acetic anhydride (5.6 g, 54.66 mmol) was added to a solution of 5-methoxy-2-methyl-phenylamine (5.0 g, 36.44 mmol) in pyridine (30 mL) and the resulting mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 5 by addition of an aqueous solution of hydrochloric acid (3 M). The resulting mixture was extracted with dichloromethane; the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 5.93 g of N-(5-methoxy-2-methyl-phenyl)-acetamide as a white solid without further purifications.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:18])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29]OS1(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:16]([O:15][C:13]([C:10]1[N:11]([CH2:29][CH2:30][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([F:18])=[CH:5][C:4]=2[Br:3])=[O:14])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[NH2:19])[S:7]1(=[O:21])=[O:20].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].C(Cl)Cl>>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:19][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[N:8]1[S:7](=[O:21])(=[O:20])[NH:6][C:10](=[O:11])[CH2:9]1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(N)cc3N)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(N2CC(=O)NS2(=O)=O)c(N)c1
Reaction time: 0.33 h

Procedure:
A solution of the title D compound, 2-(2,4-dimethoxybenzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.10 mmol) is stirred in 4 mL of TFA/CH2Cl2 (1:1) at RT for 16 h. The volatiles are evaporated and the residue is stirred in 4 mL of MeCN/water (1:1) for 20 min. The mixture is filtered through a 0.2 μM Acrodisc and the solvents are evaporated. The residue is triturated from diethylether (Et2O) to give 5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as a brown solid: [M+1]+=243.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([C:16]2[S:37][C:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C1
Yield: 91 %

Procedure:
0.40 g (1.0 mmol) of t-butyl 4-oxo-3-{[4-(trifluoromethyl)benzoyl]amino}piperidin-1-carboxylate (product of step 2) was dissolved in 0.47 g (1.2 mmol) of Lawesson's reagent, and the resulting solution was stirred under refluxing of 30 mL of toluene for 4 hours and distilled off under reduced pressure. The residue was purified by column chromatography to give 0.30 g (0.91 mmol) of the title compound in a total yield of 91%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-tert-butyl-benzene following the procedure of Example 478: MS (ESI) m/z 540.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:33])[C:23]3=[O:34])=[CH:18][CH:17]=2)[CH2:10]1.[OH2:35].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([OH:13])[CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1)[C:12]([OH:35])=[O:14]
Reactant: O
Reactant: Cn1c(=O)n(-c2ccc(CC3CC(c4c(Cl)cccc4Cl)OC3=O)cc2)c(=O)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(-c2ccc(CC(CC(O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)c2ccccc21

Procedure:
The mixture of 7 mg of 3-[4-[[5-(2,6-dichlorophenyl)-2-oxotetrahydrofuran-3-yl]methyl]phenyl]-1-methylquinazoline-2,4-dione, 0.6 mg of lithium hydroxide-monohydrate and 5 ml of tetrahydrofuran was stirred. After removing a solvent, the residue was purified by reverse phase HPLC to obtain the subject compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[I:31]I>C(OCC)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:14][CH2:15][CH3:16])=[CH:12][C:13]=1[I:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCSc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCSc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To (6-ethylsulfanylpyridin-3-yl)carbamic acid tert-butyl ester (27.6 g; 0.108 mol) and N,N,N′,N′-tetramethylethylenediamine (27 mL; 0.180 mol) in 300 mL diethyl ether at −78° C. was added dropwise n-butyllithium (100 mL of a 2.5 M solution in hexanes; 0.25 mol). The mixture was stirred mechanically for 15 minutes, warmed to 0° C.-5° C., stirred for 3 hours, cooled to −78° C. and iodine (60.6 g; 0.239 mol) in 300 mL of diethyl ether was added dropwise. The mixture was slowly warmed to room temperature, stirred overnight, and quenched with aqueous ammonium chloride and diethyl ether. The organic layer was washed with aqueous sodium metabisulfite, water, and brine, and dried over magnesium sulfate (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by CombiFlash chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide (6-ethylsulfanyl-4-iodopyridin-3-yl)carbamic acid tert-butyl ester (27.7 g; 67%), MS (ES+) m/z 381 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([NH2:8])=[O:7].C(Cl)Cl.Cl[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(N(CC)CC)C>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1)=[O:29])([OH:27])=[O:26]
Reactant: NC(=O)c1ccc(N)cc1O
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)CCCCCCCCC(=O)O)cc1O
Reaction time: 48 h

Procedure:
4-aminosalicylamide (2 g) from Example 5 is charged with 20 mL of methylene chloride. To the solution, 3.3 g of methyl 10-chloro-10-oxodecanoate is added. The reaction is initiated by addition of 2.6 mL of triethylamine. The reaction mixture is allowed to stir at ambient conditions for 2 days. Solvent is removed and the residue is acidified using 1 N HCl. The precipitate is extracted into ethyl acetate. The organic layer is further extracted with 1 N NaOH and saturated NaCl solutions. After drying over anhydrous sodium sulfate, solvent is removed. The residue is reconstituted in tetrahydrofuran (10 mL) and 10 mL of 2 N NaOH is added. The solution is brought to gentle reflux for 2 hours. The disappearance of the methyl ester is followed by HPLC. When all ester is hydrolyzed, the solution is cooled and acidified and the product is extracted into ethyl acetate. The organic layer is washed with saturated NaCl and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure and the product is obtained as off-white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.N1C=CC=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.Cl>O1CCCC1>[CH2:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)[CH3:24]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (9.3 g) in tetrahydrofuran (100 ml) were sequentially added pyridine (8.0 ml) and acetic anhydride (6.2 ml), and the solution was stirred overnight at room temperature. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. To a solution of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (9.1 g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.7 g), and the solution was refluxed for 2 hours. Ammonia solution (1 ml) and anhydrous magnesium sulfate were added on an ice bath, the solution was filtered, and then the solvent was evaporated in vacuo to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.8 g). To a solution of 4-benzyloxybenzoic acid (9.1 g) in dichloromethane (80 ml) were sequentially added oxalyl chloride (5.1 ml) and N,N-dimethylformamide (0.05 ml), the solution was stirred overnight at room temperature, then the solvent was evaporated in vacuo. To the total amount of the resulting 4-benzyloxybenzoyl chloride were sequentially added 1,4-dioxane (100 ml), N,N-diisopropylethylamine (15 ml) and ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.3 g), and the solution was refluxed for 30 minutes. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the total amount of the resulting 4-benzyloxy-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (crude product) according to an analogous synthetic method to Example 22, the title compound (13 g) was obtained.
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18]>C(O)(=O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: [NH4+]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccncc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
A 22 liter 4-neck flask fitted with a reflux condenser, thermometer and mechanical stirrer was charged with 1300 g (6.35 mol) of 4-ethoxy-3-nitropyridine hydrochloride, 2438 g (31.62 mol) of ammonium acetate and 13 1. of glacial acetic acid. The reaction mixture was refluxed for 3 hours and cooled. The volatiles were evaporated under reduced pressure and the residue was dissolved in 1N hydrochloric acid. The insoluble material was removed by filtration and the pH of the filtrate was adjusted to approximately 8.5 with concentrated ammonium hydroxide. The precipitated solid was collected by filtration, washed with water and dried in a forced air oven to provide 701 g of 3-nitro-4-aminopyridine. Yield 79.3%. mp=187°-195° C. The identity of the product was also confirmed by chromatography in a 10:1 ethyl acetate:triethylamine solvent system by comparison to a reference standard.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[C:11]([Br:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc2c(c1Br)C(=O)CCC2
Reaction time: 0.17 h
Yield: 102.4 %

Procedure:
7-Amino-1-tetralone (457 mg, 2.83 mmol) was dissolved in acetic acid (8 mL) and treated with bromine (150 mL, 2.91 mmol) dropwise. After 10 min., more bromine (17 mL) was added. Then the solvent was evaporated off to give a light brown solid. It was partitioned between Na2CO3 solution and EtOAc. From the organic phase was obtained a semi-solid (696 mg). It was dissolved in CHCl3 and flash chromatographed over silica gel (50 g) eluting with EtOAc/hexane (1:4) to afford a yellow solid (320 mg, 47% yield): mp 93-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](OCC)[CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.22 g of 3-(4-chlorobenzoyl)-acrylic acid in 40 ml of dimethylformamide were added 3.68 g of dimethyl sulfate and 1.36 g of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether. The mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the mixture by evaporation, and the residue was recrystallized from hexane to give 2.68 g of ethyl 3-(4-chlorobenzoyl)acrylate.
Reaction SMILES: Cl[C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH3:14][O:13][C:6]1[C:5]2[C:10](=[C:11]([NH2:12])[CH:2]=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1ccnc2c(N)c(Cl)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccnc2c(N)cccc12
Yield: 64.7 %

Procedure:
10% palladium on carbon (125 mg, 1.1 mmol) was added to a solution of 7-chloro-4-methoxy-quinolin-8-ylamine (Intermediate 70) (246 mg, 1.1 mmol), and ammonium formate (365 mg, 5.8 mmol) in 50% acetic acid (5 ml) and the reaction was heated under reflux for 30 min. After cooling the solvent was removed in vacuo. The residue was dissolved in EtOAc (100 ml) and washed with sat sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo to give the title compound (124 mg, 65%).