Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:15]=2)[C:12](OC)=[N:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][NH2:37])=O)=[CH:32][CH:31]=1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]2[C:34]([C:33]3[CH:38]=[CH:39][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[N:36][N:37]=[C:12]2[CH:13]1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[N:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC1=NCCN(C(=O)OC(C)(C)C)C1c1nc(-c2cccc(Cl)c2)no1
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Yield: 20.3 %

Procedure:
6-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid tert-butyl ester (284.6 mg, 0.70 mmol) and 4-methoxy-benzoic acid hydrazide (116.2 mg, 0.70 mmol) under argon in methanol (10 mL) were heated at reflux for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using 40-85% ethyl acetate in hexanes afforded the titled compound (72.5 mg, 20%). 1H NMR (CDCl3) δ (ppm): 8.07 (m, 1H), 7.96 (m, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.05 (m, 2H), 6.04 (m, 1H), 4.11 (m, 2H), 3.89 (s, 3H), 3.86 (m, 2H), 3.55 (m, 1H), 3.31 (m, 1H), 1.28 (bs, 9H).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCC=C(c1ccccc1)c1ccccc1
Product: CCOP(=O)(CC=C(c1ccccc1)c1ccccc1)OCC
Yield: 108.2 %

Procedure:
A mixture of 40.8 g (0.155 mol) of 3,3-diphenylallyl chloride (11a) and 94.48 g (0.569 mol) of triethyl phosphite was stirred with refluxing for 24 hours. The disappearance of the 3,3-diphenylallyl chloride (11a) was ascertained, before the reaction was terminated. After cooling, the reaction mixture was distilled with a Claisen flask equipped with a vigreux to obtain 55.39 g of the target compound.
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][CH:26]1[O:31][C:30]2[S:32][CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:29]=2[CH2:28][CH2:27]1>>[C:1]1([S:7]([NH:25][CH:26]2[O:31][C:30]3[S:32][CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:29]=3[CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: COC(=O)c1csc2c1CCC(N)O2
Product: COC(=O)c1csc2c1CCC(NS(=O)(=O)c1ccccc1)O2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1 starting from methyl 2-amino-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylate (Intermediate 17)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1)([O-])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:21]([C:27](Cl)=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>>[C:27]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)Cl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(=O)c1ccc(O)cc1
Yield: 82 %

Procedure:
There are charged to a half-liter reactor 9.4 g. (0.1 mole) of phenol in 150 ml. of nitrobenzene. The contents of the reactor are stirred and the mixture is cooled below 5° C. Then 27 g. (0.2 mole) of AlCl3 is added in small portions over 1/2 hour. The resulting mixture is stirred vigorously and then there is added a solution of 15.5 g. of C6H13COCl (~ 0.011 mole) in 50 ml. of nitrobenzene over an hour while the temperature is kept below 5° C. The mixture is stirred at ambient temperature for 12 hours and then the mixture is poured in 100 g. of ice and 50 ml. of concentrated HCl and stirred for 1/2 hour. The organic fraction is removed by decantation and the aqueous fraction is washed twice with CCl4 (100 ml.). The organic fractions are collected and washed three times with water (to neutrality). The solvent is evaporated under reduced pressure. The organic solution is dried over anhydrous Na2SO4. The solid obtained is recrystallized in benzene. There are obtained 16.9 g. of pure product (yield 82%), melting point: 93° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:18]([CH3:17])[CH2:19][CH2:20][OH:21])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CNCCO
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(N(C)CCO)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of 2-(methylamino)ethanol and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. 2-((6-(4-Methoxyphenylamino)pyrimidin-4-yl)(methyl)amino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and acetic anhydride (0.02 mL, 1.5 mmol) in acetonitrile was treated with triethylamine (0.1 mL, 0.8 mmol). The mixture was stirred overnight at ambient temperature and filtered to provide the title compound. 1H NMR (DMSO-d6) δ 12.27 (s, 1H), 10.04 (s, 1H), 8.11-8.20 (m, 3H), 7.87-7.95 (m, 1H), 7.58-7.66 (m, 2H), 7.48-7.56 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.27 (s, 1H), 2.06-2.12 (m, 3H).
Reaction SMILES: [C:1]1(=[C:11]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[O:14][C:12]2=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:23]1[CH2:24][CH2:25][N:20]([C:15]([CH2:16][CH2:17][CH2:18][C:11](=[C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH2:2]2)[C:12]([OH:14])=[O:13])=[O:19])[CH2:21][CH2:22]1
Reactant: O=C1CCCC(=C2CC=Cc3ccccc32)C(=O)O1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(O)C(CCCC(=O)N1CCOCC1)=C1CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.9 %

Procedure:
To a solution of 4.4 g (16.5 mmole) of 2-(1-naphthylidene)adipic anhydride (prepared as described above) dissolved in 80 ml of methylene chloride were added 1.58 ml (18.2 mmole) of morpholine, and the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was washed, in turn, with a 5% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The mixture was then freed from the solvent by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: a 30: 1 by volume mixture of methylene chloride and methanol), to afford 1.12 g of 5-morpholinocarbonyl-2-(1-naphthylidene)pentanoic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[CH2:31]([NH2:33])[CH3:32]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:33][CH2:31][CH3:32])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCN
Reactant: ClCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
5-(2-Chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (0.400 g) and ethylamine (1.2 g) were heated at 50° C. overnight and then the solution purified by chromatography using DCM to 10% 7N ammonia in methanol in DCM to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(ethylamino)ethoxy]quinazolin-4-amine; Mass spectrum MH+ 450.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]#[N:21])=[CH:15][C:3]=1[C:4]([O:6]CC(CC)CCCC)=O.[CH3:22][NH2:23]>C[O-].[Na+]>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]#[N:21])=[CH:15][C:3]=1[C:4]([NH:23][CH3:22])=[O:6]
Reactant: CN
Reactant: CCCCC(CC)COC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 124.9 %

Procedure:
The above-described method (Example 3) was repeated to stir 2-ethylhexyl 2-amino-5-cyano-3-methylbenzoate (1.00 g, 3.09 mmol) with methylamine (3.60 g, 46.3 mmol, 40% in methanol) and one drop of sodium methoxide (30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and 2-amino-5-cyano-N,3-dimethylbenzamide (730 mg, 91.4% of theory, 73.1 area % LC) was obtained as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Na+].[CH3:22][S:23]([O-])(=[O:25])=[O:24].O>CN(C=O)C>[CH3:22][S:23]([C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)(=[O:25])=[O:24]
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(S(C)(=O)=O)c2)c1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.0 g, 0.0035 mol) and methanesulfonic acid sodium salt (3.24 g, 0.021 mol) in 15 mL of DMF was heated at 140° C. for 24 hours. After the mixture was cooled, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.45 g (40% yield) of product as a yellow solid: mp: 140-142° C.; Anal. Calc'd. for C17H17N3SO2: C, 62.36; H, 5.23; N, 12.83; S, 9.79. Found: C, 62.16; H, 5.31; N, 12.74; S, 9.86.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH3:20])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a mixture of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (50 mg, 0.137 mmol) and potassium carbonate (76 mg, 0.548 mmol) in DMF (2 mL) was added iodomethane (26 μL, 0.411 mmol) at RT. After 3 days, the reaction mixture was partitioned between ethyl acetate and water. The resultant biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was crystallised from ethyl acetate to give the title compound (31.8 mg, 61%) as a cream solid. The mother liquors were evaporated, the residue was dissolved in DCM and subjected to flash chromatography (SiO2, gradient 70 to 100% ethyl acetate in cyclohexane) to afford a further quantity of the title compound (17.6 mg, 34%). LCMS (Method A): RT=3.78 min, [M+H]+=380.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)Cl)c1
Reaction time: 16 h

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.NO.[N:33]1C=CC=CC=1>C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:33][O:29][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(-c2noc(-c3ccc(OC)cc3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 3 (1.0 equiv.), hydroxylamine hydrochloride (1.5 equiv.), pyridine (2.0 equiv.) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo. The product 1-[4,5-bis(4-methoxyphenyl)isoxazol-3-yl]-4-methoxybenzene was obtained as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:31])[CH2:20][O:21][C:22]1[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([O:21][CH2:20][CH:19]([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1cnc(OCC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid (CAS 1174323-38-6; WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=428.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[S:18]([O:10][CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[OH:11])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1cccc([C@H](O)CO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(C)c2)cc1
Reaction time: 17 h
Yield: 84.2 %

Procedure:
To a stirred solutioll of (S)-1-(3-methylphenyl)-1,2-ethanediol (1.78 g, 11.7 mmol) in pyridine (35 ml) was added p-toluenesulfonyl chloride (2.46 g, 12.9 mmol), and 4-dimethylaminopyridine (1.58 g, 12.9mmol) at 0° C. and the reaction mixture was stirred at 0° C. to rt for 17 h. The reaction mixture was acidified with 6 N HCl aqueous solution and extracted with CH2Cl2. The extract was washed with water and brine, dried (Na2SO4), and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography (silica gel: 100 g, ethyl acetatelhexane:1/9 to 1/3) to afford 2.63 g (73%) of desired product as light yellow oil. Its optical purity was 97% ee by HPLC employing a chiral stationary phase (chiral pak AS, Daicel Chemical Industries, eluted with n-hexane/EtOH:98/2; detection time:: 55 min for (R)-isomer 59 min for (S)-isomer).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[O-]CC.[Na+].[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([C:24]([CH3:34])([CH3:33])[CH2:25][C:26]2([C:29]([F:32])([F:31])[F:30])[CH2:28][O:27]2)[CH:23]=1>CCO>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:28][C:26]([OH:27])([C:29]([F:30])([F:32])[F:31])[CH2:25][C:24]([C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=2[O:35][CH3:36])([CH3:33])[CH3:34])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(C(F)(F)F)cc(Cl)c1=O)C(F)(F)F
Temperature: 85 °C

Procedure:
A mixture of 3-chloro-5-trifluoromethylpyridin-2-ol (135 mg, 0.68 mmol) in 1 mL of EtOH was added to 0.13 mL of a 1M sodium ethoxide solution in ethanol and was heated to 85° C. for 5 minutes in a sealed vial. The mixture was cooled to room temperature, 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane was added, and the mixture heated to 85° C. overnight in a sealed vial. The volatiles were removed in vacuo and the residue diluted with water and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified on PLC plate (hexanes-EtOAc (8:2)) to give 125 mg of 3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-5-trifluoromethyl-1H-pyridin-2-one as a solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].C[O-].[Na+].[C:13](=O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5](=[NH:6])[O:14][CH3:13])[CH3:2]
Reactant: O=C=O
Reactant: CCOC(C#N)OCC
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Yield: 95 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70-75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77-78° C. at 20-22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0-5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [N:1]1[C:14]2[C:5](=C3[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][C:8](=O)[C:7]3=[O:16])[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[CH:4]1[C:5]2[C:7](=[O:16])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[N:1]=[CH:2][CH:3]=1
Reactant: O=C1C=Cc2ccc3ncccc3c2C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ccccc2-c2ncccc21
Yield: 53.5 %

Procedure:
Following the procedure described in Example 608, Part B, 8.2 g (0.04 mole) of 1-azaphenanthren-5,6-dione and 165 ml of 10% sodium hydroxide were heated in a bath at 80°-90° for 3 hours. Identical workup yielded 3.88 g, m.p. 140°-142° of pure 4-azafluoren-9-one.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:27][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[C:5]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]3=[N:3][C:2]=4[NH2:1])=[CH:19][CH:18]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: BrCC1CCC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC4CCC4)cc3)cc12

Procedure:
2-(4-(Cyclobutylmethoxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using (bromomethyl)cyclobutane. 1H NMR (Acetone-d6): δ 8.79 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.47 (s, 1H), 7.26 (d, 1H), 7.16 (d, 2H), 6.82 (d, 2H), 3.90 (d, 2H), 3.23 (t, 2H), 3.06 (t, 2H), 2.68-2.79 (m, 1H), 2.49 (s, 3H), 2.05-2.14 (m, 2H), 1.80-1.98 (m, 4H). LRMS [M+H]=398.2