Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7](C)[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].N=O.CC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.[BH4-].[Na+]>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: N=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CO
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
In accordance with one aspect of the present invention, there is provided a method of preparing azithromycin of formula (I) comprising the steps of: (a) reducing 6,9-imino ether of formula (III) dissolved in methanol with 5 to 7 mole equivalents of NaBH4 at −20 to −10° C., treating the reaction mixture with an acidic aqueous acetone solution of citric acid, and adjusting the solution pH to 10.5 to 12.0 to obtain a crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II); and
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1cccs1

Procedure:
92 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(3,4-dichlorophenyl)piperazine (44 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15](=[N:17][O:18][CH2:19][CH3:20])[CH3:16])=[C:11]([Br:21])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15](=[N:17][O:18][CH2:19][CH3:20])[CH3:16])=[C:11]([Br:21])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCON=C(C)COc1c(Br)ccc(C(=O)OCC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCON=C(C)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.820 g (1.90 mmol) of ethyl 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoate was dissolved in a mixture of 8 ml of THF and 8 ml of water, and 0.085 g (2.10 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, and 6 N HCl was added. The mixture was then extracted with methylene chloride. The organic phase was dried using Na2SO4 and concentrated, giving 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoic acid in the form of a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:26])[CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11].[Na].[OH-].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:26])[CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Agent: Cl
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (15.7 g, 42.5 mmol) in methanol (100 ml) was added 2N aqueous sodium, hydroxide solution (43 ml, 86 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (11.7 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>CO.C(OCC)(=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:21]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.079 g, 0.300 mmol) in methanol (1.2 mL) was added with 1H-indole-3-carboxaldehyde (0.0523 g, 0.300 mmol) and piperidine (0.00255 g, 0.0300 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain an orange crude product as a solid. This solid was suspended in ethyl acetate and thereby washed to obtain the objective (Z)-2-[(1H-indol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0128 g, 10%).
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][O:4]1.[CH:10]([OH:12])=[O:11]>>[Cl:1][CH2:2][C:3](=[O:4])[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][O:11][CH:10]=[O:12]
Reactant: CC1(C)CCOC1=CCl
Reactant: O=CO
Product: CC(C)(CCOC=O)C(=O)CCl
Yield: 87 %

Procedure:
29.2 g (0.2 mol) of 2-chloromethylene-3,3-dimethyltetrahydrofuran, in 100 ml of formic acid, are heated at 60° for 5 hours. Fractional distillation produces 34 g (0.174 mol, 87%) of 1-chloro-3,3-dimethyl-5-formyloxypentan-2-one with a boiling point of 110°/0.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16](=O)[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH:17]([CH3:19])[CH3:18])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: CC(C)C(=O)CBr
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(N)n2cc(C(C)C)nc12

Procedure:
The title compound was prepared according to the procedure described in the step 2 in EXAMPLE 1 (METHOD B) from methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, METHOD B, Step 1) and 1-bromo-3-methylbutan-2-one (Synthesis, 1976, 194-196) using N,N-dimethylformamide as a solvent.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:30][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])=[CH:23][CH:22]=1
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 76.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.65 ml (4.96 mmol) of 4-toluoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 910 mg of the desired compound (76.6%, colorless powder), mp: 110.0°-111.0° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:5]=1[C:6]#[N:7].[CH2:19]([OH:21])[CH3:20]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:5]=1[C:6](=[NH:7])[O:21][CH2:19][CH3:20]
Reactant: COc1ccc(CN2CCOCC2)cc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(CN2CCOCC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-5-morpholin-4-ylmethyl-benzonitrile (300 mg, 1.292 mmol) in anhydrous ethanol (30 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo to dryness to afford crude ethyl 2-methoxy-5-morpholin-4-ylmethyl-benzimidate hydrochloride. meso-1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diamine (150 mg, 0.533 mmol), triethylamine (373 μL, 5 mmol) and ethanol (10 mL) were added and the resulting mixture was heated at reflux for 12 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×30 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-20% methanol in ethyl acetate to afford 4-{3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxy-benzyl}-morpholine (164 mg, 62%). LR-MS (APCI): 496 [(M+H)+].
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[CH2:11]([P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])[P:12]([O:16][CH3:17])(=[O:15])[O:13][CH3:14]>>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:11]([P:12]([O:13][CH3:14])(=[O:15])[O:16][CH3:17])[P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Reactant: C=Cc1ccc(CCl)cc1
Product: C=Cc1ccc(CC(P(=O)(OC)OC)P(=O)(OC)OC)cc1

Procedure:
Following the General Synthetic Procedure B, 4-vinylbenzylchloride is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 4-vinylbenzyl-methanebisphosphonate that is then hydrolyzed to yield 4-vinylbenzyl-methanebisphosphonic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.C(N(CC)CC)C.O1CCOCC1>O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@@H:10]2[CH3:14])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(Br)cn1
Temperature: 110 °C
Yield: 78.8 %

Procedure:
A 250 mL pressure vessel was charged with (S)-4-(tert-butoxycarbonyl)-2-methylpiperazine (4.17 g, 21.84 mmol, Sigma-Aldrich, St. Louis, Mo.), 5-bromo-2-chloropyrimidine (4.22 g, 21.84 mmol, Combi-Blocks, San Diego, Calif.), triethylamine (6.09 mL, 43.7 mmol), and 50 mL of dioxane. The tube was sealed and heated at 110° C. for 24 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The organics were dried (MgSO4) and concentrated to give an oil that was purified via column chromatography (120 g silica, 0 to 30% EA/Hex) to give tert-butyl (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate (6.15 g) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3ccsc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccsc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 63 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-thien-3-yl-5,6-dihydrophenanthridine (0.28 g, 0.58 mmol), cyclohexene (13 mL, 10.5 mmol), and 1 M boron tribromide in dichloromethane (3.5 mL, 3.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4) to yield 4-[(6-ethyl-8-fluoro-2-thien-3-ylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.17 g, 63%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[CH2:21][S:22]([NH:25][CH2:26][C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[CH2:21][S:22]([NH:25][CH2:26][C:27]([OH:29])=[O:28])(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CNS(=O)(=O)CC1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(CS(=O)(=O)NCC(=O)O)c2cc(OCc3ccccc3)ccc2O1

Procedure:
1.4 g of methyl [(6-benzyloxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]acetate are stirred at RT for 4 h in 50 ml of methanol and 15 ml of 2N NaOH. After removing the methanol, the residue is washed with EA and acidified with HCl. It is extracted with EA and the solvent is removed in vacuo after drying. 500 mg of the acid having a melting point of 167-169° C. are obtained.
Reaction SMILES: [NH2:1][NH2:2].COC(=O)[CH:6]([C:14]1[CH:19]=[N:18][C:17]([C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:16](Cl)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[OH-].[Li+].Cl>C1COCC1.O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:17]2[C:16](=[N:15][C:14]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])=[CH:19][N:18]=2)[NH:2][N:1]=1
Reactant: COC(=O)C(c1cnc(C(=O)c2ccccc2Cl)c(Cl)n1)c1ccccc1F
Reactant: NN
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccccc1Cc1cnc2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
Hydrazine (54 mg, 1.7 mmol) was added to a solution of [6-Chloro-5-(2-chloro-benzoyl)-pyrazin-2-yl]-(2-fluoro-phenyl)-acetic acid methyl ester (0.59 g, 1.4 mmol) in 50 mL THF at 0° C., and the reaction mixture was stirred and allowed to warm to room temperature. Lithium hydroxide (27 mg, 5.0 mmol) was added, and the reaction mixture was stirred for 64 hours at room temperature. Concentrated aqueous HCl (1 ml) was then added, and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, extracted with diethyl ether, and the combined organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via chromatography using 5% ethyl acetate in hexanes as the eluent to afford 0.151 g of 3-(2-Chloro-phenyl)-6-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyrazine. Mass Spec. M+H=340.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1ccc(-n2ncc(C(=O)Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C#N)c3)c2C)cc1
Yield: 41.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-methylphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.4 g), the title compound (0.94 g) was obtained, melting point: 243° C.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)(=O)C>Cl.O>[CH3:15][O:14][C:12]([C:10]1[S:11][C:7]([CH2:6][CH:5]=[S:4])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(CCSC(C)=O)s1
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(CC=S)s1
Yield: 98.1 %

Procedure:
A solution of 4.89 g (20 mmol) of 9d in 1N methanolic HCl (75 mL) was heated at reflux for 2 hours. The reaction was diluted with water (50 mL) and the methanol was removed by concentration, in vacuo. The aqueous residue was extracted with ether (2×75 mL). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to provide the product as a yellow oil (3.93 g, 97% yield).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1Cl)[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]>CN(C=O)C.COCCO>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[N:2]([CH3:3])[CH3:1])[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]
Reactant: CNC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: COCCO
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N(C)C)cc21
Reaction time: 7 h
Yield: 88 %

Procedure:
13 g of dimethylamine were dissolved in a mixture of DMF (20 cm3) and methyl cellosolve (20 cm3). 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid were added and the mixture was heated, whilst stirring, in an autoclave at 120°-130° C. for 7 hours. After cooling, the solution was concentrated to dryness in vacuo and the residue was taken up in 20 cm3 of water. The solid was filtered off and recrystallised from methyl cellosolve (30 cm3). 3.9 g of 6-chloro-7-dimethylamino-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 210° C., were obtained.
Reaction SMILES: FC(F)(C(F)(F)C(F)(F)C(F)(F)F)CCC(CCCCCC=C)C(OCC)=O.C(OCC)(=O)CC(OCC)=O.ICCCCCC=C.I[CH2:49][CH2:50][C:51]([F:63])([F:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[C:54]([F:57])([F:56])[F:55].[CH2:64]([C:66]1([C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH:84](CCCCCCC(F)(F)C(F)(F)F)[C:85]([OH:87])=[O:86])[C:74]2[C:69](=[CH:70][C:71]([OH:101])=[CH:72][CH:73]=2)[S:68][CH2:67]1)[CH3:65]>>[CH2:64]([C:66]1([C:102]2[CH:103]=[CH:104][C:105]([OH:108])=[CH:106][CH:107]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH:84]([CH2:49][CH2:50][C:51]([F:63])([F:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[C:54]([F:57])([F:56])[F:55])[C:85]([OH:87])=[O:86])[C:74]2[C:69](=[CH:70][C:71]([OH:101])=[CH:72][CH:73]=2)[S:68][CH2:67]1)[CH3:65]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Agent: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared from diethyl malonate, 7-iodo-1-heptene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 9 and the allyl compound prepared in Example 13, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH2:13])[CH2:8]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCC(N)C2
Product: COc1cccc2c1CCC(NC(C)=O)C2
Yield: 20 %

Procedure:
Using a procedure similar to that described in Example 1, 0.30 g of 5-methoxy-2-amino-tetralin yielded 0.06 g (20%) of 5-methoxy-2-acetamido tetralin following treatment with acetic anhydride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])O[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]>C(O)(=O)C>[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:38](=[O:39])[C:33]7=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:41][CH:40]=[C:34]7[C:35]6=[O:36])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc([N+](=O)[O-])cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1
Yield: 73 %

Procedure:
A mixture of 9,9-bis(4-aminophenyl)fluorene (3.5 g, 10 mmol) and 40 ml of acetic acid was stirred and then 4-nitrophthalic anhydride (4.1 g, 21 mmol) was added to the mixture. The resulting mixture was stirred and heated under reflux for 7 hours. After cooling, the beige-colored precipitate was filtered, washed with acetic acid (2×100 ml) and then with water (500 ml). The washed precipitate was recrystallized from dimethyl-fromamide-methanol to provide the title compound as an off-white powder (5.1 g, 73% yield) having a melting point of 360°-363° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].C=O.[BH3-][C:17]#N.[Na+]>>[CH3:17][N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 97.7 %

Procedure:
This compound was prepared by General Method 3 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.15 g, 6.38 mmol), paraformaldehyde (1.92 g, 64.1 mmol) and NaBH3CN (1.95 g, 30.9 mmol) to afford 1.21 g (98%) of 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine: Rf 0.83 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, 1H, J=9.0, 2.6), 7.65 (d, 1H, J=3.4), 6.56 (d, 1H, J=8.9), 4.27 (t, 2H, J=4.6), 3.46 (t, 2H, J=4.5), 3.05 (s, 3H).