Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19](=[O:34])[CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1>O1CCOCC1.CO>[CH3:41][N:38]1[CH2:37][CH2:36][N:35]([C:5]2[CH:6]=[C:7]([C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][N:15]([C:19](=[O:34])[CH2:20][CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH2:16]4)=[CH:11][CH:10]=3)[N:8]=[C:3]([NH2:2])[N:4]=2)[CH2:40][CH2:39]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
2 mL of 4.0 N HCl in 1,4-dioxane was added to a solution of tert-butyl 4-{2-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}piperidine-1-carboxylate (25 mg, 0.045 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the product as an HCl salt (25 mg, 98%). Analytic LCMS (M+H)+: m/z=450.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]=1[CH3:12].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:13][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:26])[F:27])[CH:17]=2)(=[O:24])=[O:23])=[N:10][C:11]=1[CH3:12]
Reactant: Cc1nc(N)ccc1COCCF
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1nc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1COCCF

Procedure:
This material was prepared in analogy to example 1 from 5-(2-fluoro-ethoxymethyl)-6-methyl-pyridin-2-ylamine (0.05 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.073 g) as a light yellow gum (39 mg g). MS (ESI−): 391.2 ([M−H]−)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([S:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21

Procedure:
An appropriate indole is N-deprotonated and the resulting anion reacted with phenylsulfonyl chloride to provide the corresponding 1-phenylsulfonylindole. This protected indole may be purified or treated directly with an appropriate base, typically a lithium amide such as lithium diisopropylamide, and then reacted with an appropriate tropanone to provide the corresponding 3-hydroxy-3-(1-phenylsulfonylindol-2-yl)-8-azabicyclo[3.2.1]oct-2-ane.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH:9]2[NH:26][CH2:25][C:24](=O)[NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][C:10]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CO>C1COCC1.O>[N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH:26]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCNCCNCCNCCN1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CC2CNCCNCCNCCNCCNCCN2)cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
A solution of BH3 in THF (100 mmol) was added dropwise to a stirred suspension of 3-(4-nitrobenzyl)-2,6-dioxo-1,4,7,10,13,16-hexaazacyclooctadecane (4) (10 mmol) in THF (50 ml) at 0° C. under nitrogen atmosphere. The solution was heated at reflux for 36 hours. Methanol was added slowly to the solution at 0° C. after which the solvent was removed and the residue was dissolved in methanol (50 ml); the resulting mixture was cooled at 0° C. and gaseous HCl was bubbled through the solution and then the mixture was refluxed for 12 hours. The resulting precipitate was collected washed with ether to give a white powder. The solid was dissolved in water and was loaded on a column of DOWEX 1X-8 anion-exchange resin (OH− form). The column was eluted with water; alkaline fractions were collected, and the water was removed under vacuum to give pale yellow oil. The yield was 55%.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N+:11](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)#[CH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:26]=[N:11][N:5]3[CH:6]=[CH:7][C:2]([C:1]([O:9][CH3:10])=[O:8])=[CH:3][C:4]=23)=[CH:28][CH:29]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2ncc(-c3ccc(C(F)(F)F)cc3)c2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of methyl isonicotinate (500 μL, 4.23 mmol, 1.0 equiv.) in 2 mL DMF was added O-(2,4-dinitrophenyl)hydroxylamine (1 g, 5.02 mmol, 1.2 equiv.) and the resulting solution was allowed to stir overnight at 40° C., during which time the reaction became heterogeneous. The mixture was allowed to cool to rt before being diluted with 10 mL DMF, then treated with 4-ethynyl-α,α,α-trifluorotoluene (863 μL, 5.29 mmol, 1.25 equiv.) and potassium carbonate (877 mg, 6.35 mmol, 1.5 equiv.). The mixture was allowed to stir overnight at 100° C. The resulting mixture was allowed to cool to rt, and then the solvent was removed under reduced pressure. The residue was diluted with water and the aqueous layer was extracted with EtOAc five times. The combined EtOAc extracts were washed once with water, once with brine, and then dried with MgSO4, filtered, and the solvent removed under reduced pressure. The material was purified by silica gel chromatography, eluting with hexanes/EtOAc (Rf=0.26 in 5:1 hexanes/EtOAc) to give 335 mg (25% yield) I-1. 1H NMR (400 MHz, CDCl3, δ): 8.52 (m, 2H), 8.23 (s, 1H), 7.72 (s, 4H), 7.40 (dd, J=1.59, 7.50 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][CH:14]([NH2:16])[CH3:15].Cl.Cl.C[Si](C)(C)CCOC[N:25]1[C:29]2[N:30]=[CH:31][N:32]=[C:33]([C:34]3[CH:35]=[N:36][N:37]([C:39]4([CH2:43][C:44]#[N:45])[CH2:42][NH:41][CH2:40]4)[CH:38]=3)[C:28]=2[CH:27]=[CH:26]1>>[Cl:11][C:10]1[C:2]([N:41]2[CH2:42][C:39]([CH2:43][C:44]#[N:45])([N:37]3[CH:38]=[C:34]([C:33]4[C:28]5[CH:27]=[CH:26][NH:25][C:29]=5[N:30]=[CH:31][N:32]=4)[CH:35]=[N:36]3)[CH2:40]2)=[CH:3][C:4]([F:12])=[C:5]([CH:9]=1)[C:6]([NH:16][CH:14]([CH3:15])[CH3:13])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1F
Reactant: CC(C)N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Product: CC(C)NC(=O)c1cc(Cl)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 4,5-dichloro-2-fluorobenzoic acid (Ark Pharm, Inc., Cat. #: AK-29091), 2-propanamine and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=493.2/495.2. 1H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 9.09 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 7.86 (dd, J=8.0, 2.5 Hz, 1H), 7.78 (m, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.23 (m, 1H), 6.64 (d, J=12.0 Hz, 1H), 4.77 (d, J=9.0 Hz, 2H), 4.51 (d, J=9.0 Hz, 2H), 3.75 (s, 2H), 4.00 (m, 1H), 1.12 (d, J=6.5 Hz, 6H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1[N:15]1[C:19](=[O:20])[CH:18]=[C:17]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[N:16]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]>ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1[N:15]1[C:19](=[O:20])[C:18]([Cl:4])=[C:17]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[N:16]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(=O)OCC)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2c(Cl)c(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(=O)OCC)c1

Procedure:
4.45 ml (0.055 mole) of sulfuryl chloride are added dropwise in 15 min at -50° C to a cooled solution of 34.4 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-2-ethoxycarbonyl-3-(2-chloro-5-myristoylamino-anilino)-3-pyrazolin-5-one (compound 19) in 100 ml dichloromethane.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]2[C:7]([NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:15]=[C:14]2[C:7](=[CH:6][CH:5]=1)[NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH:13][C:16](=[O:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Product: CC(=O)NCCc1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
5-Nitrotryptamine (6 mmol) is dissolved in pyridine (15 ml) and treated with acetic anhydride (7 mmol) 20 min at 27° C. The solvents are removed in vacuo, the residue taken into a small amount of methanol and passed through a short plug of silica with 5% methanol-chloroform eluent. Product-containing fractions are pooled, evaporated and dried thoroughly at <0.1 mm Hg.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8]C)(=[O:4])[CH:2]=[CH2:3].O=[CH:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20]O)O)O)O)O.[C:22]([O-])(O)=O.[Na+]>>[CH2:11]=[CH:12][C:14]1[CH:2]=[CH:1][CH:20]=[CH:18][CH:16]=1.[C:1]([O:5][CH:6]([CH2:7][CH3:8])[CH3:22])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCC
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])O
Agent: [Na+]
Product: C=CC(=O)OC(C)CC
Product: C=Cc1ccccc1
Temperature: 145 °C
Reaction time: 5 h

Procedure:
Block Copolymerization To a 3 necked round bottom flask was added n-butyl acrylate (25 mL), glucose (0.119 grams), NaHCO3 (0.139 grams) and a polystyrene TEMPO terminated (2.068 g, Mn=6,000). This was purged with argon gas bubbling through the solution for 25 minutes. Then the flask was heated by immersion into a preheated oil bath of 145° C. After 5 hours, poly(styrene-b-n-butyl acrylate) was obtained with Mn=29,594, and PD=2.18 and conversion of 62 percent.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1C.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:17][C:6]1[CH:7]=[C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:3]=[CH:4][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-3-methylnitrobenzene (15.5 g), imidazole (6.8 g), and sodium carbonate (11.1 g) was heated at 100° for 24 hours in dimethylformamide (DMF). The mixture was then concentrated in vacuo, the residue was acidified to pH1 with 4M hydrochloric acid, and the resulting solution was extracted with chloroform (2×25 cm3). The aqueous phase was basified to pH10 with 2.5 M sodium hydroxide solution and the mixture was extracted with chloroform (3×100 cm3). The dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallised from ethyl acetate to afford 1-(3-methyl-4-nitrophenyl)imidazole, m.p. 112°-115°, (10.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30].O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2([F:30])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[O:11]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1OC(F)(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 90.1 %

Procedure:
To a solution of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (6.76 g, 22.00 mmol) in anhydrous dichloromethane (35 ml) at 0° C. pyridine (1.80 ml, 22.00 mmol) was added, followed by the dropwise addition of cyanuric fluoride (2.0 ml, 24.20 mmol) in dichloromethane (4.0 mL). The reaction mixture was stirred for 100 minutes at 0° C. Water (35 mL) was added to the reaction mixture and it was stirred for 10 min at 0° C. The resulting slurry was filtered through a pad of Celite and it was washed with dichloromethane. The filtrate was partitioned with water and the dichloromethane layer was washed with water and it was dried over anhydrous sodium sulfate. Filtration and concentration provided 3-(4-chloro-3-nitrophenyl)-3-fluoro-2-benzofuran-1(3H)-one, (6.10 g, 90% yield) as a crystalline solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 8.34 (d, J=2 Hz, 1H), 8.20 (dd, J1=8 Hz, J2=0.8 Hz, 1H), 8.01-7.94 (m, 3H), 7.86 (td, J1=8 Hz, J2=1.2 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H); MS (EI) for C14H7ClFlNO4: 306 (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C@H:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H].[ClH:25]>[Pd].C(OCC)(=O)C.C(O)C.C(O)(=O)C>[ClH:25].[CH2:15]([NH:12][C@H:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C[C@@H](N)CCC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)C[C@@H](NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-3-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine hydrochloride (35.5 g) was neutralized with cold 2N sodium hydroxide (155 ml) and the mixture was extracted once with ethyl acetate (310 ml). The extract was washed once with brine (155 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford (S)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (30.1 g). A mixture of (S)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (30.1 g), 10% palladium on carbon (50% wet; 5.96 g), acetic acid (0.89 ml), benzaldehyde (31.6 ml), and ethanol (300 ml) was stirred at ambient temperature for 3 hours. Then, hydrogen was introduced to the mixture and stirring was continued for an additional 1.5 hours. The catalyst was filtered off and washed with ethanol. Removal of the solvent in vacuo gave the residue, which was dissolved in ethyl acetate (423 ml). To this solution was added, with mechanically stirring in an ice-bath, 4N hydrogen chloride in ethyl acetate (77 ml). After stirring at ambient temperature for 1.5 hours, the mixture was filtered and the cake was washed with ethyl acetate (50 ml). The product was dried in vacuo to give (S)-N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine hydrochloride (47.3 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.C1CCN2C(=NCCC2)CC1.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>C(#N)C>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.2 g, 0.68 mmol) in acetonitrile was added DBU (0.19 mL, 1.28 mmol) followed by 1,2,4-triazole (0.053 g, 0.76 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography using EtOAc in pet. ether to give title product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthalenecarboxylate (0.3 g, 0.861 mmol), tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.0345 mmol), 2 M Na2CO3 (4 mL) and 4-hydroxyphenyl boronic acid (0.143 g, 1.03 mmol) in ethylene glycol dimethyl ether (5 mL) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water and EtOAc. The EtOAc layer was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 50% EtOAc) gradient to afford 0.23 g (92%) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1 H), 8.76 (d, J=9.0 Hz, 1 H), 8.20 (m, 2 H), 8.07 (d, J=7 Hz, 1H), 7.93 (m, 1 H), 7.66 (d, J=9 Hz, 2 H), 7.58 (t, J=8 Hz, 1H), 6.88 (d, J=9 Hz, 2 H), 4.42-4.37 (m, 2 H), 1.37 (t, J=7 Hz, 3 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:11]=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:26](OC(C)(C)C)(=[O:31])[CH2:27][C:28]([O-])=[O:29].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:21]4[CH:24]=[CH:25][C:18]([CH:15]5[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]5)=[CH:19][CH:20]=4)[C:28](=[O:29])[CH2:27][C:26]3=[O:31])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(C2CCC(=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CCC(c2ccc(C3C(=O)CC(=O)N3c3ccc4[nH]cnc4c3)cc2)CC1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.803 g, 6.04 mmol), 4-(4-oxocyclohexyl)benzaldehyde (1.5 g, 6.04 mmol), mono-tert-butyl malonate (0.97 g, 6.04 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.95 g, 6.04 mmol) and sodium tert.-butoxide (0.60 mg, 5.35 mmol) according to method 5.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[F:26][C:27](S(=O)(=O)C1C=CC=CC=1)=[CH2:28]>C1(C)C=CC=CC=1.ClCCl>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:28]=[C:27]([F:26])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: C=C(F)S(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(F)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.6 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)-oxazolidin-2-one (Reference Example 2) (0.7 g, 1.9 mmol) and (1-fluoroethenyl)-phenylsulfane dioxide (0.7 g, 3.8 mmol) (D. P. Mathews and J. R. McCarthy, JOC 55 (9), 1990, p 2973) were suspended/dissolved in toluene (5 ml) and heated to reflux under stirring for 2 days. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with phosphate buffer (pH 7) and dried over sodium sulfate. Chromatography on silica gel with hexanes/acetone (1:1) gave 28 mg (4%) of the title compound as a colourless solid (Rf ˜0.25, TLC:hexanes/acetone, 1:1). The major product was the corresponding 5-fluoro-1,2,3-triazoyl compound with an Rf of ˜0.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][CH:5]([CH2:7][O:8][CH:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22]C=[CH:20][CH:19]=2)C(=O)CC([O-])=O)[CH2:4][O:3]1.[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)([O-:35])=[O:34]>C(O)C>[CH3:32][C:26]1[NH:25][C:26]([CH3:32])=[C:27]([C:28]([O:30][CH2:22][CH2:23][C:18]2[CH:17]=[CH:16][C:9]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:1])([CH3:24])[O:6]3)=[CH:20][CH:19]=2)=[O:29])[CH:39]([C:38]2[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=2)[C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OCC(COC(CCc2ccccc2)C(=O)CC(=O)[O-])O1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC3COC(C)(C)O3)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 95 %

Procedure:
A solution of 13.2 g. (0.039 mol) of 4-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyphenylethylacetoacetate (5), 4.7 g (0.41 mol) of methyl β-aminocrotonate, and 6.2 g (0.41 mol) of 3-nitrobenzaldehyde in 80 mL of ethanol was heated at reflux for 12 h. Solvent was removed in vacuo and the residue purified by medium pressure chromatography on silica gel (80% ether-hexane) to give 21 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyphenyl]ethoxycarbonyl)-1,4-dihydropyridine (6) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#N.[OH-:18].[K+].[OH2:20]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:20])=[O:18]
Reactant: N#CCc1ccccc1Oc1cccc(F)c1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccccc1Oc1cccc(F)c1

Procedure:
2-(3-Fluorophenoxy)benzeneacetonitrile (23 g.), dissolved in 80 ml of ethanol, was heated to reflux for 2 hours with a solution of 20 g. potassium hydroxide in 40 ml of water. The ethanol was evaporated, the residue taken up in water, extracted with ether and acidified to give the title compound, m.p. 81°-84°. ##STR14##
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:20])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:20])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC2(COc3ccc(N)cc3OC2)OC1=O
Product: CC(C)N1CC2(COc3ccc(NS(C)(=O)=O)cc3OC2)OC1=O

Procedure:
By reacting the oxazolidinone obtained in Step A with methanesulfonyl chloride and employing the other reaction conditions and procedure described in Example 87, Step A, there is obtained 3'-isopropyl-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one.