Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:6]=[C:7]([Cl:11])[CH:8]=2)[NH:3]1.[OH-].[Na+].[O:22]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(Cl)cc(Oc3ccccc3F)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cc(Cl)cc1Oc1ccccc1F

Procedure:
A mixture of 2-oxo-5-chloro-7-(2-fluorophenoxy)indoline (4.0 g.), sodium hydroxide (1.2 g.), dioxane (25 ml.) and water (25 ml.) was refluxed under heating for 15 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water (200 ml.), washed with diethyl ether twice (200 ml. and 100 ml.) and then filtered. To the filtrate was added a mixture of diethyl ether (200 ml.) and ethyl acetate (200 ml.) and the mixture was adjusted to pH 4 with 5% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (200 ml.), dried over magnesium sulfate and then evaporated under reduced pressure. The resultant product was recrystallized from ethanol (30 ml.) to give 2-[2-amino-3-(2-fluorophenoxy)-5-chlorophenyl]acetic acid (2.7 g.), mp 154° to 156° C. Thus obtained compound was dissolved in 1N aqueous sodium hydroxide (9.13 ml.) and lyophilized to give sodium 2-[2-amino-3-(2-fluorophenoxy)-5-chlorophenyl]acetate (3.15 g.). mp>250° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:9][C:7]2[C:6]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[CH:5][N:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-5-(4-methoxybenzyloxy)pyridin-4(1H)-one (Intermediate 62, 3.48 g, 13.32 mmol) in DMF (100 mL) at room temperature was added 4-methoxybenzyl chloride (1.987 mL, 14.65 mmol) followed by potassium carbonate (2.273 mL, 39.96 mmol). The reaction mixture was stirred for 1 hour at room temperature then heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine. The ethyl acetate layer was concentrated to afford an oil. To the oil was added 1N HCl and a light brown solid crashed out. This was collected by filtration. The solid was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a brown solid (2.62 g, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCCCC2OCCO2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred solution of 2-(5-bromopentyl)-1,3-dioxolane (4.38 g, 19.6 mmol) in dimethyl formamide (30 mL) was added 4-hydroxybenzaldehyde (3.00 g, 24.4 mmol) and potassium carbonate (4.52 g, 32.8 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to afford an oil. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (1.92 g, 36%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:5]2[CH2:6][C:7]3[C:12]([CH2:13][C@H:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.[OH-].[K+]>CO.[Pd]>[CH3:27][CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]([OH:28])[CH2:21][CH2:20][C@H:19]1[C@H:2]([OH:1])[CH2:3][C@H:4]2[C@@H:5]1[CH2:6][C:7]1[C:12]([CH2:13]2)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Yield: 88 %

Procedure:
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetic acid (2.5 g, 0.008 mol) in dry methanol (25 ml) was treated with potassium hydroxide (0.5 g, 0.008 mol), then with 5% Pd/C (0.5 g, 20% wt) under hydrogen overnight at room temperature. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The residues was diluted with 50 m ethyl acetate and 50 ml saturated sodium bicarbonate aqueous. The mixture was phase separated and the organic layers was extracted with 50 ml saturated sodium bicarbonate aqueous. The aqueous layers were combined and then 3N HCl was added slowly until pH=˜2. The aqueous layer was extracted with 100 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization. The titled compound was obtained in a crystalline form. Yield: 88%
Reaction SMILES: [CH3:1][CH:2]([CH:6]([S:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])[CH2:7][CH3:8])[C:3]([OH:5])=O.[NH2:18][CH:19]1[C:34](=[O:35])[N:21]2[C:22]([C:31]([OH:33])=[O:32])=[C:23]([CH2:26][O:27][C:28](=[O:30])[NH2:29])[CH2:24][S:25][C@H:20]12>>[CH3:1][CH:2]([CH:6]([S:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])[CH2:7][CH3:8])[C:3]([NH:18][CH:19]1[C:34](=[O:35])[N:21]2[C:22]([C:31]([OH:33])=[O:32])=[C:23]([CH2:26][O:27][C:28](=[O:30])[NH2:29])[CH2:24][S:25][C@H:20]12)=[O:5]
Reactant: CCC(C(C)C(=O)O)S(=O)c1ccc(O)cc1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CCC(C(C)C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
540 mg. of 2-methyl-3-(p-hydroxyphenylsulfinyl) pentanoic acid and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 144 mg. of 7-[2-methyl-3-(p-hydroxyphenylsulfinyl)pentanamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][NH:18]C(=O)O)=[C:10]3[S:22][C:23]4[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[ClH:32]>C(O)C>[ClH:32].[ClH:32].[ClH:32].[NH2:18][CH2:17][CH2:16][NH:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:30][CH3:31])[CH2:1][CH3:2])[N:7]=[C:8]3[C:24]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=4[S:22][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c(NCCNC(=O)O)ccc31)Sc1cc(O)ccc1-2
Agent: Cl
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1cc(O)ccc1-2
Temperature: 3 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To an ice-cold solution of 29.4 g (59.1 mmol) of [2-[[2-[2-(diethylamino)ethyl]-8-hydroxy-2H-[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]amino]ethyl]-carbamic acid; 1,1-dimethylethyl ester and 800 mL of absolute ethyl alcohol was slowly bubbled anhydrous hydrogen chloride until the temperature reached 12° C. The mixture was cooled to 3° C., and the bubbling process was repeated three times, then the mixture was warmed to 25° C. After stirring overnight, the solids were collected by filtration then stirred for 30 minutes at 5° C. with a solution of 250 mL of water and 800 mL of ethyl alcohol. The mixture was diluted with an additional 250 mL of ethyl alcohol and stirred at 5° C. for 5 hr, then at -5° C. for 30 minutes. The solids were collected by filtration, washed successively with diethyl ether then hexane, and dried over phosphorus pentoxide at 2 mm/40° C./2 hr then at 2 mm/25° C./48 hr to give 27.6 g (90.5%) of 4 as the trihydrochloride salt and solvated with 0.5 equivalents of water, mp 260°-264° C. (dec), 99.4% pure by HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].ClC1C=CC=C(C(OO)=[O:22])C=1>C(OCC)(=O)C>[N+:1]1([O-:22])[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 40 h
Yield: 81.4 %

Procedure:
tert-Butyl 2-pyridinecarboxylate (14.0 g, 78 mmol) was dissolved in ethyl acetate (200 ml), and 3-chloroperbenzoic acid (ca. 77%, 26.2 g, 117 mmol) was added thereto. The reaction mixture was stirred at room temperature for 40 hrs. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate-acetone (1:1, v/v) to give the titled compound (12.4 g, 81%).
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.N(OCCC(C)C)=O.[Cl:23][Si](C)(C)C>[Cl-].C([N+](CC)(CC)CC)C>[Cl:23][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Reactant: C[Si](C)(C)Cl
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 10 h
Yield: 78.5 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol), tetraethylammonium chloride (0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol) were added to chlorotrimethylsilane (4.0 g, 36.8 mmol), and the mixture was heated to 50-60° C. and stirred for 10 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the mixture was adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give 2,6-dichloropurine as a white powder (0.35 g, yield 78.3%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([N:2]([CH3:3])[CH3:1])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 24a) from 1-(3-is dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), a 2M solution of dimethylamine in tetrahydrofuran (10 ml) and a solution of 3-bromophenylacetic acid (2.15 g) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as an oil (2.89 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:23]([C:22]2[CH:21]=[N:20][N:13]3[C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:27])([F:1])[F:26])=[CH:9][CH:8]=4)=[N:11][C:12]=23)=[O:24])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 618.3 [(M+H+]; mp 212° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1([CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]1[C:19]([OH:21])=[O:20].[C:23]([S:26][CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:25])[CH3:24].Cl>C(Cl)Cl>[C:23]([S:26][CH2:27][CH2:28][C:29]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:22])([CH3:9])[CH:11]1[C:19]([OH:21])=[O:20])=[O:30])(=[O:25])[CH3:24]
Reactant: CC1(C)c2ccccc2NC1C(=O)O
Reactant: CC(=O)SCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCCC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.93 g of triethylamine are added to the suspension of 0.7 g of 3,3-dimethylindoline-2-carboxylic acid hydrochloride in 20 ml of methylene chloride and the resulting solution is cooled to -10°. The solution of 0.51 g of 3-acetylthiopropanoyl chloride in 5 ml of methylene chloride is added dropwise and the mixture stirred at -5° to -10° for 1 hour and at room temperature for 3 hours. It is cooled to 0° and treated with 10 ml of 3N hydrochloric acid. The organic layer is separated and the aqueous solution further extracted with methylene chloride. The combined methylene chloride solutions are dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-3,3-dimethylindoline-2-carboxylic acid as a foam.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)#[CH:18]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C@H:10]4[CH2:14][CH2:15][CH2:16][C@@H:9]34)=[N:6][CH:7]=2)=[CH:20][CH:21]=1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Reactant: C#Cc1ccc(F)cc1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2ccc(F)cc2)cn1
Yield: 77 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (100 mg, 0.305 mmol) (Example 1, step 6) and 1-ethynyl-4-fluorobenzene to yield 75 mg (77%) of the title compound as a viscous yellow oil; MS: m/e=321.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(Cl)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 374. 1HNMR (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=1.52 Hz), 7.66 (d, 2H, J=8.55 Hz), 7.55-7.53 (m, 2H), 7.46 (d, 2H, J=8.55 Hz), 7.39 (d, 1H, J=8.56 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.13 (d, 2H, J=8.24 Hz), 6.53 (d, 1H, J=3.05 Hz), 5.39 (s, 2H), and 1.21 ppm (s, 9H). Elemental Analysis for C25H24ClN: Calculated: C, 78.05; H, 6.60; N, 3.64. Found: C, 78.02; H, 6.27; N, 3.53.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=2)=[CH:17][C:18]=1[F:23]
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)c(F)c3)ccn2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 77.6 %

Procedure:
A solution of N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (500 mg, 1.47 mmol) in CH2Cl2 (10 mL) was treated with ammonium cerium(IV) nitrate (1.64 g, 2.99 mmol) and the resultant mixture was stirred at RT overnight. The reaction mixture was washed with water, concentrated in vacuo and purified by silica gel chromatography to yield 4-(4-amino-3-fluorophenoxy)pyridin-2-amine (250 mg, 77% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J=6.0 Hz, 1H), 6.88 (dd, J=9.0, 2.0 Hz, 1H), 6.80 (t, J=8.7 Hz, 1H), 6.68 (m, 1H), 6.06 (dd, J=4.5, 1.8 Hz, 1H), 5.84 (s, 2H), 5.75 (d, J=1.5 Hz, 1H), 5.08 (s, 2H); MS (ESI) m/z: 220.3 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].ClC[CH2:14][CH2:15][O:16][CH3:17]>>[CH3:10][O:9][C:5]1[C:4]([O:11][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COCCCCl
Reactant: COc1cccc(CO)c1O
Product: COCCOc1c(CO)cccc1OC

Procedure:
Analogously to Method F, 2.67 g of 2-hydroxymethyl-6-methoxyphenol and 2.19 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=3.08.
Reaction SMILES: Cl.[C:2]1([CH2:15][CH2:16][NH2:17])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH:3]=1)[O:11][CH2:10][CH2:9][CH2:8]3.[CH3:18][N:19]=[C:20]=[O:21]>N1C=CC=CC=1>[C:2]1([CH2:15][CH2:16][NH:17][C:20]([NH:19][CH3:18])=[O:21])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH:3]=1)[O:11][CH2:10][CH2:9][CH2:8]3
Reactant: CN=C=O
Reactant: NCCc1coc2ccc3c(c12)CCCO3
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)NCCc1coc2ccc3c(c12)CCCO3

Procedure:
To a suspension of 0.01 mole of 2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethylamine hydrochloride in five (5) ml of pyridine, 0.011 mole of methylisocyanate is added dropwise with stirring. The reaction mixture is stirred for one (1) hour at 80° C., then poured on ice/water. After classical work up and purification, the title compound is obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([CH2:20][O:21][CH3:22])[C:8]=2[CH2:7]1)[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[C:26]1([S:23]([C:4]([CH:6]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=4)[N:9]([CH2:20][O:21][CH3:22])[C:8]=3[CH2:7]2)([CH3:5])[CH2:3][OH:2])(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(C(=O)OC)S(=O)(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To 402 mg (0.84 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2yl)-propionic acid methyl ester in 6 mL of THF, 1.0 mL (1.0 mmol, 1.2 eq) of LiAlH4 in THF was added at RT. After 30 min, the reaction mixture was poured into water and extracted with EtOAc, dried over Na2SO4, and evaporation of the solvent afforded (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propan-1-ol as a colorless oil, MS: 465 (MNH4+). The crude material was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([Cl:19])[N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[CH3:20][NH:21][CH3:22]>C1COCC1>[Cl:19][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[CH:4][CH:5]=2)[N:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CBr)cc2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(-c2ccc(CN(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(bromomethyl)phenyl)-6-chloroisonicotinate (0.533 g, 1.56 mmol) in THF, dimethylamine (7.8 mL, 2M solution in THF) was added and reaction mass stirred at rt for overnight. On completion, reaction mass concentrated and crude obtained was purified by column chromatography over silica gel obtaining pure methyl 2-chloro-6-(4-((dimethylamino)methyl)phenyl)isonicotinate (0.48 g, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[NH:15][O:16][C:17](=[O:19])[N:18]=2)[CH:9]=1)(C)(C)C.Cl>CCO>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[NH:15][O:16][C:17](=[O:19])[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2nc(=O)o[nH]2)c1
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-c2nc(=O)o[nH]2)c1
Temperature: 60 °C

Procedure:
A 1 L flask equipped with a magnetic stir bar and heating mantle was charged with [3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-carbamic acid tert-butyl ester (60.0 g, 0.22 mol) and EtOH (800 mL). The resulting suspension was then treated with HCl gas (31 g, 0.86 mol) at ambient temperature over 20 minutes. The reaction mixture was then heated to 60° C., until starting material was consumed (1.5 h). The reaction mixture was cooled in an ice-bath and the resulting solid was collected via vacuum filtration. The filter pad was washed with EtOH (75 mL) and air dried to yield the title compound as an off white solid.
Reaction SMILES: C(O[C:4](=O)[CH:5]([CH3:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)C.[C:26](O)(=O)C>[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:24](=[CH2:26])[CH:5]([CH3:4])[CH2:6][N:7]([CH2:8][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[C:14]=2[N:15]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C)CN(CC1CCCC1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Product: C=C1Nc2cnc(Cl)nc2N(CC2CCCC2)CC1C

Procedure:
To a solution of 2.18 g (0.0059 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentylmethyl-amino]-2-methyl-propanoic acid ethyl ester in 40 mL of acetic acid was added 2.0 g (0.0358 g-atom) of iron powder. The mixture was heated at 80 degrees for 2.5 hours, and then filtered through Celite while still hot. The filter cake was washed with 100 mL of ethyl acetate. The filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium hydroxide, 100 mL of water and 100 mL of brine. The aqueous layers were back extracted with 100 mL of ethyl acetate. The ethyl acetate layers were combined, dried, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane—hexanes to give 1.16 g of (rac)-2-chloro-9-cyclopentylmethyl-7-methyl-6-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine (VI-55) as light brown crystalline solid.