Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH3:10][O:11]C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]=[O:11])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC=O
Solvent: Cc1ccccc1
Product: O=CNCc1ccc(Cl)nc1
Yield: 86.7 %

Procedure:
15 g of 91.7% pure (0.1 mol) 2-chloro-5-cyanopyridine were hydrogenated in a mixture of 70 ml of methylformate and 50 ml of toluene analogously to Example 1. After analysis by gas chromatography, 2-chloro-5-(formylaminomethyl)pyridine had formed in a yield of 86.7% of theory. 2-Chloro-5-(aminomethyl)pyridine (3.6% of theory) and di(2-chloro-5-methylpyridyl)amine (2.0% of theory) were identified as by-products. The crude product was boiled under reflux with 30 ml of 20% strength NaOH for 2 hours. After extraction with CH2Cl2 and concentration, the residue was distilled in vacuo. 12 g of 98.7% pure goods, corresponding to 83.1% of theory, based on the 2-chloro-5-cyanopyridine, were obtained.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 4-biphenylacetic acid (10 g, 47 mmol) in methanol (150 mL) was added concentrated HCl (3 mL). The mixture was heated under reflux for 16 hours, cooled to rt, and the solvent was evaporated. Chromatography of the residue over silica gel (petroleum ether followed by ethyl acetate/petroleum ether 1/4) gave 4-biphenylacetic acid methyl ester (10.4 g, 98%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:43]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH2:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(N)=O)noc3c2F)C[C@@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 210) and ammonia (0.5 M in dioxane).
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[N:5]1([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:2]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)[CH2:6][CH2:7]1)[CH:3]=[CH2:4]
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: C=CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) was added to a stirred solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (1.242 g, 5 mmol) and DIPEA (2.183 mL, 12.50 mmol) in dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 24 h. This was diluted with dichloromethane (20 mL), washed with water (2×25 ml) and saturated sodium chloride solution (20 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.700 g, 48.5%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][C:18]([NH2:23])=[N:17][C:16]=2[N:15]([CH2:24][C:25]2[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=2)[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][C:18]([NH2:23])=[N:17][C:16]=2[N:15]([CH2:24][C:25]2[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=2)[CH:14]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCCCNC(=O)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2cc(C#CCCCN)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of {5-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-pent-4-ynyl}-carbamic acid tert-butyl ester (see previous example, 33 mg) in DCM (1.0 mL) was treated with TFA (0.2 mL) at rt for 10 min. The reaction mixture was concentrated, taken in water (1.5 mL), washed with EtOAc (1.5 mL), made alkaline with sat. aq. NH4OH (0.5 mL), and back-extracted into EtOAc (25 mL). Washing (NH4OH 1M), drying (Na2SO4) and concetration affroded the title compound. tR=4.37 min. 1H NMR (CDCl3) δ 8.15 (s, 1H), 6.97 (s, 1H), 5.25 (s, 2H), 3.72 (s, 3H), 2.94 (m, 2H), 2.48 (t, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.80 (quint., 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[CH3:16])(=O)[CH3:8].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O>[CH2:7]([NH:10][C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[CH3:16])[CH3:8]
Reactant: CC(=O)Nc1c(C)nn(C)c1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CCNc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Under an atmosphere of nitrogen, lithium aluminum hydride, LAH, (4.3 g, 113.6 mmol) was added portionwise to a vigorously stirred solution of 4-acetamido-1,3,5-trimethyl-1H-pyrazole (9.5 g, 56.8 mmol) of step A. After stirring at ambient temperature for 2 hours, the mixture was heated at reflux for 1 hour and the excess LAH was decomposed by the careful addition of 4.3 mL of H2O, 4.3 mL of 1N NaOH, 12.9 mL of H2O and 54 g Na2SO4. The solids were filtered and the filtrate concentrated in vacuo to give 7.26 g of title compound as a brown oil (91% crude yield).
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A mixture of spray-dried KF (307 mg, 5.3 mmol), intermediate 12 (150 mg, 0.53 mmol) and catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 170-180° C. for 30 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (92 mg, 68%), mp 146-150° C. 1H NMR (400 MHz, DMSO-d6): δ 8.90 (1H, d, J=4.0 Hz), 8.21 (1H, d, J=9.6 Hz), 8.15 (1H, d, J=8.0 Hz), 7.84 (1H, t, J=6.8 Hz), 4.36-4.40 (1H, m), 1.38 (3H, d, J=6.4 Hz); LC-MS (negative ion mode): m/z 255 (M−H)−.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:15]([O-])(=[S:17])[CH3:16].[K+]>C1COCC1>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][CH:2]2[C:15](=[S:17])[CH3:16]
Reactant: CC1(C)CCC(Br)c2cc(Br)ccc21
Reactant: CC([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=S)C1CCC(C)(C)c2ccc(Br)cc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene naphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol ) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16]#[N:17])[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O.[H][H]>[Pd].CO>[NH2:17][CH2:16][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)C(C#N)c1ccc(OC)c(OC)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)C(CN)c1ccc(OC)c(OC)c1
Yield: 32.8 %

Procedure:
A MeOH solution (100 mL) containing methyl 3,4-dimethoxyphenylcyanoacetate (1.2 g, 5.1 mmol), TFA (1 mL), and 50 mg of 10% Pd/C was shaken on a Parr shaker for 20 hours under 30 psi of hydrogen. The reaction was filtered, concentrated, dissolved in H2O, and extracted 2× with Et2O. The pH was adjusted to ~10 and the mixture extracted 3× with EtOAc. The EtOAc fractions were dried over Na2SO4 and concentrated to yield 400 mg (32%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]([OH:33])=[O:32])[CH2:27][CH:26]2[C:28]([OH:30])=[O:29])=[CH:21][CH:20]=1)([O-])=O.C(N)CC.[OH-].[Na+].NC(N)=O.Cl>O1CCCC1>[NH2:16][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]([OH:33])=[O:32])[CH2:27][CH:26]2[C:28]([OH:30])=[O:29])=[CH:21][CH:20]=1
Reactant: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(N)=O
Solvent: CCCN
Solvent: C1CCOC1
Product: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g of N,N'-dicyclohexylcarbodiimide are added to a solution of 2.5 g of 1-(4-nitrophenyl)-1,2-cyclopropanedicarboxylic acid in 50 ml of tetrahydrofuran and the mixture is stirred for 1 hour at room temperature. A solution of 0.83 ml of propylamine and 10 ml of tetrahydrofuran is then added dropwise at room temperature to the resultant suspension. The mixture is then stirred at room temperature until reaction is complete. The solvent is evaporated off, the residue is taken up in water and 1 equivalent of sodium hydroxide solution, and the precipitated urea is removed by filtration. The filtrate is acidified with 1 equivalent of hydrochloric acid and extracted twice with methylene chloride. The organic phases are washed once with water, dried over magnesium sulfate and concentrated. Recrystallisation of the residue from ethyl acetate/ether/petroleum ether affords white crystals of the title compound (b) with m.p. 154°-155° C. and Rf=0.45 on thin-layer silica gel plates in the system methylene chloride/methanol/glacial acetic acid (40:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 105.1 %

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (50 g, 0.246 mol) in MeOH (500 mL) at 0° C. was added NaBH4 (9.3 g, 0.246 mol) portionwise. After 1 h, the reaction was concentrated in vacuo, diluted with water and extracted with DCM. The combined extracts were dried over MgSO4 and concentrated in vacuo to give (3-bromo-4-fluorophenyl)methanol (53 g). 1H NMR (400 MHz, CDCl3) δ 7.58-7.56 (m, 1H), 7.28-7.25 (m, 1H), 7.09 (t, J=4.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 2H), 1.82 (t, J=5.6 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])=[CH:36][CH:35]=1
Reactant: COc1ccc(O)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1ccc(OCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 44.1 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 4-(methyloxy)phenol (124 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (21.0 mg, 44%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+:10].C([Li])CCC.[Na+].[C:17]([CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:17]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][C:1](=[O:6])[CH:2]=1.[Na+:10].[C:17]([CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])CCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane in 50 mL of tetrahydrofuran and 25 mmol of 4-benzoylbutyric acid sodium salt in 100 mL of tetrahydrofuran. 4-Benzoylbutyric acid sodium salt was prepared by reacting the acid (25 mmol) with hexane washed NaH (17.5 mmol) in tetrahydrofuran at 0° C. for 25 minutes. The crude product was flash chromatographed using CH2Cl2 /MeOH/CH3CO2H (99/1/0.1-97.5/2.5/0.1) to give a solid which was recrystallized from ethyl acetate (m.p. 134°-137° C.). 1H NMR (DMSO-d6) δ1.1-1.2 (m, 1H), 1.4-1.6 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.9 (ABq, 2H), 4.85 (s, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[Cl:12][C:13]1[C:22]([NH2:23])=[C:21]([NH:24][CH2:25][C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:12][C:13]1[C:22]2[N:23]=[C:1]([CH3:2])[N:24]([CH2:25][C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:27]=3)[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 61.8 %

Procedure:
Pyridine hydrochloride (0.020 g, 0.19 mmol), triethyl orthoacetate (2.3 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and treated according to the method of Part A of Example 26 to provide 2.307 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[O:13][CH2:12][C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]>CC#N>[CH3:16][N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:14]=2[O:13][CH2:12][C:11]1=[O:15]
Reactant: COC(=O)c1cccc2c1OCC(=O)N2C
Solvent: CC#N
Product: CN1C(=O)COc2c(C(=O)O)cccc21

Procedure:
prepared by saponification of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid methyl ester. LC-MS: tR=0.64 min; [M+CH3CN+H]+=249.3.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:15][CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:12][CH:13]=[CH2:14])[CH:19]=[CH2:18]
Reactant: C=CCC(O)C1CCC2(CC1)OCCO2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(CC=C)C1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)but-3-en-1-ol (436 mg, 2.05 mmol), prepared in the previous step, was added to a suspension of sodium hydride (104 mg, 4.12 mmol, 95%) dropwise at 0° C. under argon. After the complete addition, the reaction mixture was allowed to reach room temperature and stirred 1 hour. Allyl bromide (0.35 mL, 4.05 mmol) was added dropwise and the mixture stirred overnight at room temperature. It was poured onto ice cooled saturated NaHCO3 solution. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to afford the product.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl-].[Cl-].[Ca+2:68].Cl.[C:70]([OH:82])(=[O:81])[CH2:71][C:72]([CH2:77][C:78]([OH:80])=[O:79])([C:74]([OH:76])=[O:75])[OH:73].[NH4+].[OH-]>CO.O>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Ca:68].[C:70]([OH:82])(=[O:81])[CH2:71][C:72]([CH2:77][C:78]([OH:80])=[O:79])([C:74]([OH:76])=[O:75])[OH:73]
Reactant: [Ca+2]
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: Cl
Solvent: O
Solvent: CO
Product: [Ca]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.66 g of amphotericin B (938γ/mg of activity-equivalent to 10 g of chemical activity) suspended in 2.5 liters anhydrous methanol containing 11.1 ml of 5% CaCl2 in methanol (equivalent to 200 mg Ca ion) is solubilized by means of 1.75 ml of 5.8 N HCl (pH 3.9). To the resulting solution is added 10.9 g of reagent grade citric acid. H2O (equivalent to 10 g anhydrous citric acid) to form a mixture of pH 2. The pH of the mixture is adjusted to about 7 by the addition of 7.9 ml concentrated NH4OH. The mixture is then heated to 45°-50° C. and slurried for 1 hour and thereafter is cooled to room temperature, filtered and the wet cake dried overnight under vacuum at 45°-50° C. to yield 10 g of complex.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=O)C.C([O-])([O-])=O.[K+].[K+].O>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a solution of 0.9 g (3.49 mmol) of methyl 6-acetoxymethyl-2-naphthoate in 100 mL of MeOH was added 0.5 g (3.62 mmol) of K2CO3 and 1 mL of H2O. The mixture was stirred at room temperature for 30 min before being evaporated to dryness. The residue was taken up in 50 mL of EtOAc and 30 mL of H2O. The organic layer was dried (Na2SO4) and evaporated to give 0.76 g (100% yield) of methyl 6-hydroxymethyl-2-naphthoate as white crystals: mp 123°-124° C.; IR (mull) 3250, 1720, 1300, 1200, 1130, 1100, 1040, 1020, 920, 900, 840, 820, 760 cm-1 ; 1H NMR (CDCl3) δ2.13 (s, 1, OH), 3.98 (s, 3, CO2CH3), 4.88 (s, 2, CH2OH), 7.3-8.7 (m, 6, ArH); MS calcd for C13H12O3 216.0786, found 216.0787.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:4]=2[N:3]=1>N.CO>[Br:29][C:26]1[CH:27]=[CH:28][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[C:5]=2[CH:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Br)cc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.176 g (0.359 mmole) of 89 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature <40° C.), The resulting solid was recrystallized from MeOH to give 0.097 g (2 crops, 74%) of 90 as white crystals. MP 152°-153° C. MS (El) m/e 361.9685 (10%, M+ =361.9669). 1H NMR (DMSO-d6): d 8.43 (d, 1, 7-H, J7-5 =2.0 Hz), 7.59 (d, 1, 4-H, J4-5 =8.5 Hz), 7.43 (dd, 1, 5-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.34 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.27 (d, 1, 3'-OH, J3'-3'OH 4.5 Hz), 4.45 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14, (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.00 (m, 1, 4'-H, J4'-5' =J4-5" =3.5 Hz), 3.70 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 140.70 (C2), 140.49 (C3a), 134.02 (C7a), 125.95 (C5), 120.46 (C4), 116.01 (C7), 115.87 (C6), 88.99 (C1'), 86.32 (C4'), 71.40 (C2'), 69.79 (C3'), 61.15 (C5').