Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:20]([CH3:22])C)[NH:5][S:6]([NH:9]C(OCC1C=CC=CC=1)=O)(=[O:8])=[O:7].[CH3:24]O>[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:5][S:6]([NH2:9])(=[O:7])=[O:8])[CH2:20][CH2:22][CH3:24]
Reactant: CO
Reactant: COC(=O)C(NS(=O)(=O)NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-DL-valine methyl ester (28.5 g) in methanol (200 ml) under nitrogen was cooled to 0° C. and 1.8 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 2 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (ethyl acetate/hexane, 1:1) to afford 17.2 g (96%) of N-(aminosulfonyl)-DL-valine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =isopropyl; R3 =H) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.ClC1C=C(C(OO)=[O:21])C=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnccc1OCC1CC1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of 3-Bromo-4-cyclopropylmethoxy-pyridine (Example 53a, 1 g, 4.38 mmol) in dichloromethane was added 3-Chloro-benzenecarboperoxoic acid (1.47 g, 6.58 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 250 mL dichloromethane and extracted with 75 mL of an aqueous solution 1M sodium bicarbonate. The organic layers was collected, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (954 mg, 89%) as a white solid. MS (ESI, m/z): 244.2 (M+H+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Si:11]([O:6][CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: C[C@@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Butane-1,3-diol (5.00 mL), tert-butylchlorodimethylsilane (8.82 g), N,N-dimethylpyridin-4-amine (0.34 g) and triethylamine (23.2 mL) were suspended in dichloromethane (60 mL) and stirred at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organics were dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 5-10% ethyl acetate/hexane) to furnish to afford the title compound (8.33 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:38]=[C:36]([CH3:37])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (596 mg, 2.00 mmol) in dichloromethane (8 ml) was treated with 1,1′-carbonyldiimidazole (364 mg, 2.25 mol) and the solution was stirred at room temperature for 15 minutes. The N-hydroxy-acetamidine (Chem.Ber.; 17; 1884; 2746) (148 mg, 2.00 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat under a nitrogen atmosphere for 90 minutes. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound (385 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:22]([C:21]1[C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][C:18]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:19][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)cc1NCC1CCNCC1
Reaction time: 3 h

Procedure:
4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyridin-4-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (91 mg, 0.17 mmol) was dissolved in CH2Cl2 (2.5 mL). TFA (2.5 mL) was added and the reaction was stirred for 3 h. The volatiles were removed and the resultant residue was redissolved in EtOAc and poured into 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified by SiO2 chromatography (1:10:89, NH4OH:CH3OH:CH2Cl2) to afford 5-nitro-N4-piperidin-4-ylmethyl-N2-(2-trifluoromethoxy-benzyl)-pyridine-2,4-diamine as a yellow solid, m/z 426.4 (M+H)+ (28 mg, 39%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:19]([N:21]=[C:22]=NCCCN(C)C)C.CN(CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.CNC>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
4-(Benzyloxycarbonylamino)butyric acid (0.74 g, 3.12 mmol) was dissolved in N,N-dimethylformamide, then 1-(dimethylaminopropyl)-3-ethylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.13 mmol), 1-hydroxybenzotriazole (0.48 g, 3.13 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 2.40 ml, 4.80 mmol) were added, followed by stirring at room temperature for 3 days. The reaction liquid was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1 to 40:1) to obtain a yellow solid (0.68 g, 82%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([CH2:55][NH2:56])[OH:54]>CN(C=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:56][CH2:55][CH2:53][OH:54])=[O:17])=[CH:18][CH:19]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)cc2)s1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)NCCO)cc2)s1
Reaction time: 5 h

Procedure:
To 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzoic acid (Example 74b) (0.1 g, 0.36 mmol) in DMF (1 ml) is added HATU (0.14 g, 0.36 mmol) followed by DIPEA (0.07 ml, 0.36 mmol) and ethanolamine (0.022 ml, 0.36 mmol). After 5 hours, the reaction mixture is filtered and the precipitated product is washed with ethanol and dried under vacuum to give the titled compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 4-fluoro-2-methoxy-1-nitrobenzene and N,N-dimethylpiperidin-4-amine. m/z 280.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:18](OC)=[O:19])[CH:11]=[C:12]([CH:17]=2)[C:13](OC)=[O:14])[CH2:5][O:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1([CH2:6][O:7][C:8]2[CH:17]=[C:12]([CH2:13][OH:14])[CH:11]=[C:10]([CH2:18][OH:19])[CH:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1cc(OCC2(C)COC2)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(COc2cc(CO)cc(CO)c2)COC1

Procedure:
The title compound is prepared from dimethyl 5-((3-methyloxetan-3-yl)methoxy)isophthalate by reduction with lithium aluminum hydride in tetrahydrofuran. LC (method 7): tR=0.69 min; Mass spectrum (ESI+): m/z=239 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)=[NH:5])C.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:9]1[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]4[N:5]=[C:29]([CH2:30][N:31]([CH3:33])[CH3:32])[NH:28][N:27]=4)[CH:7]=3)[NH:11][N:10]=1)[CH:24]=[CH:23]2
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc4cc(OC)ccc4c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(-c5n[nH]c(CN(C)C)n5)cc34)ccc2c1
Temperature: 95 °C
Yield: 5.6 %

Procedure:
To a suspension of ethoxy[3-(6-methoxy(2-naphthyl))(1H-indazol-5-yl)]methanimine (0.430 g, 1.13 mmol) in methanol (5 mL) was added N-amino-2-(dimethylamino)acetamide (0.396 g, 3.38 mmol) and 4.3 M sodium methoxide (0.578 mL, 2.49 mmol). The mixture was heated in a sealed tube at 95° C. for 16 h. The solvent was removed using a rotary evaporator and gave a solid residue. Purification of the residue by preparative HPLC (10–80%, acetonitrile/water) gave the title compound (0.025 g, 5% yield): 1H NMR (DMSO-d6) δ 13.95 (br s, 1H), 13.40 (br s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.09 (t, 2H), 8.00 (t, 2H), 7.68 (d, 1H), 7.39 (d, 1H), 7.21 (dd, 1H), 3.90 (s, 3H), 3.60 (s, 2H), 2.22 (s, 6H); ES-MS (m/z) 399 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][OH:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][P:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[P:21]([O:17][CH2:16][CH2:15][SiH2:14][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25]
Reactant: OCC[SiH2]C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)OCC[SiH2]C(c1ccccc1)c1ccccc1

Procedure:
The reaction described in Example 10 was carried out using 2-(diphenylmethylsilyl)-ethanol (2.25 g), diethylphosphorochloridate (1.35 g), and pyridine (0.6 g) in carbon tetrachloride (10 ml). Diethyl 2-(diphenylmethylsilyl)ethyl phosphate was obtained as a colourless oil (1.35 g) (C17H23Si O4P requires: C, 60.5%; H, 7.1%; Found: C 63.4%; H, 7.8%).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C@@H:15]3[O:20][C:19]4=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:18]4[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CC(C)=O.Cl>O>[N+:24]([C:22]1[N:21]=[C:19]2[N:18]([CH:23]=1)[CH2:17][CH2:16][C@H:15]([CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)=[CH:28][CH:27]=1)[O:20]2)([O-:26])=[O:25]
Reactant: COC1(OC)CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
(R)-7-[4-(4,4-Dimethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5.16 g), acetone (100 ml) and water (17 ml) were mixed. A 6 N hydrochloric acid aqueous solution (41 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The remaining water layer was ice-cooled and neutralized by adding a 20% sodium carbonate aqueous solution. After being stirred at the same temperature for 10 minutes, the precipitated crystal was collected by filtration. The crystal thus obtained was dried at 60° C. to afford the title compound as a yellow solid (4.57 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH3:12]>[OH-].[Na+]>[Cl:1][C:2]1[C:3]2[S:8][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc2c(Cl)cccc12
Temperature: 120 °C

Procedure:
To a solution of 11.8 g. 2-chlorothiophenol (Aldrich, 15566-7) dissolved in aqueous sodium hydroxide (4.0 g./50 ml water) is added chloracetone (9.3 g.). After heating for 1 hour the reaction is cooled and extracted with methylene chloride. The extract is dried (MgSO4) and concentrated to an oil. The oil is added to polyphosphoric acid (100 g.) and slowly heated to 120° C. The mixture is added to ice and extracted with ethyl ether. The ether extract is washed with water (twice); dried (MgSO4) and concentrated to an oil. The oil is purified by distillation.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH2:10])[CH2:3]2.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:12]=[O:13]>CN(C=O)C.C(N(CC)CC)C>[CH2:14]([NH:11][C:12]([NH:10][CH:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=NCc1ccccc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)NC1CN2CCC1CC2
Yield: 548.3 %

Procedure:
To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.06 g, 0.16 mmol) was suspended in dry CH2Cl2 (1.5 mL) under an argon atmosphere in a screw cap vessel. K2CO3 (0.044 g, 0.32 mmol) was added followed by benzyl chloroformate (0.046 mL, 0.032 mmol). The suspension was stirred for 18 h at room temperature. H2O and CH2Cl2 were added and the phases were separated. The water phase was washed with CH2Cl2 (×2) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CD3OD) δ 198.3, 161.0 (dd), 157.8 (dd), 155.8, 151.1, 141.1, 138.0, 136.2, 135.0, 132.8, 132.7, 129.5, 129.1, 129.0, 128.7, 127.3 (dd), 126.0 (dd), 122.3, 120.6, 116.7, 112.9, 112.6 (dd), 105.7 (dd), 67.6, 19.7
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.S(Cl)([Cl:20])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([Cl:20])=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ccc(C(=O)Cl)cc2cc1OC

Procedure:
To a solution containing 15.0 g. of 6,7-dimethoxy-2-naphthoic acid and one drop of dimethylformamide in 200 ml. of benzene was added 25 ml. of thionyl chloride. After heating one hour under reflux the mixture was evaporated to dryness in vacuo. Additional benzene was added and evaporation repeated to give 6,7-dimethoxy-2-naphthoyl chloride which was used directly in the preparation of 6,7-dimethoxy-2-naphthamide as described hereinabove in Example 113.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32](=[O:34])[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[C:32]([CH2:33][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:13]([O:12][CH2:11][CH:2]2[CH2:3][CH2:4][N:5]3[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:1]2)=[O:14])=[CH:16]1)(=[O:34])[CH3:31]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21
Reaction time: 72 h
Yield: 4 %

Procedure:
A stirred solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (300 mg, 0.96 mmol) in acetone (10 ml) was treated with anhydrous potassium carbonate (270 mg, 2 mmole) and bromoacetone (150 mg, 1.1 mmole) and kept at room temperature for 3 days. The mixture was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×25 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The pale yellow oil obtained was crystallised from ether to afford the title compound (E31) as a beige solid (14 mg) mp 139°-1420C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]([C:16]1[C:17]([OH:37])=[C:18]([CH:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH:27]2[CH2:32][O:33]C(=O)C)[C:19]([O:24][CH3:25])=[CH:20][C:21]=1[O:22][CH3:23])=[O:15].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:37][C:17]2[C:16]([C:14](=[O:15])[CH:13]=1)=[C:21]([O:22][CH3:23])[CH:20]=[C:19]([O:24][CH3:25])[C:18]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C(F)(F)F)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (15% solution in hexane, 2.2 mL, 5 mmol) in THF (10 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (1.08 mL, 5.1 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (41)(1.44 g, 2.5 mmol) in THF (10 mL) was added dropwise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8 to 9. The aqueous layer was extracted with chloroform (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(2-chloro-4-trifluoromethyl-phenyl)-3-oxo-propionyl]-2-hydroxy-4,6-dimethoxy-phenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as an oil (1.3 g, 90.2%). This ester was dissolved in conc. HCl (10 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8 to 9. The aqueous layer was extracted with chloroform (25×3 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the compound, (+)-trans-2-(2-chloro-4-trifluoromethylphenyl)-8-(2-hydroxymethyl-1-methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)c(N)c1
Yield: 106 %

Procedure:
A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21](C)([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[CH2:32]1COCC1.[BH4-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:29])[C:15]2[CH:24]=[CH:23][C:22]3[CH:21]([CH3:25])[CH:20]([CH3:32])[CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CC(C)C3C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (7.4 mmol) of methyl 2-hydroxy-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate and 100 ml of a methanol/THF (50/50) mixture were introduced into a round-bottomed flask and 140 mg (3.7 mmol) of sodium borohydride were added in small amounts. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 1.6 g (55%) of the expected compound, with a melting point of 92°-93° C., was recovered.