Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+]([C:27]1[CH:28]=C(S([O-])(=O)=O)C=[CH:31][CH:32]=1)([O-])=O.[Na+].C(=O)/C=C/C>O>[OH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[C:9]([F:11])=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[C:7]=2[CH:28]=[CH:27][C:32]([CH3:31])=[N:6]3)[CH2:13][CH2:14]1
Reactant: Nc1cc(N2CCC(O)CC2)c(F)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: C/C=C/C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(N3CCC(O)CC3)c(F)cc([N+](=O)[O-])c2n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
2-Nitro-4-fluoro-5-(4-hydroxy-1-piperidyl)aniline (20 g) was added to 60% sulfuric acid prepared from 40 ml of concentrated sulfuric acid and 48 ml of water, and 13.2 g of sodium m-nitrobenzenesulfonate was added to the mixture. The resulting mixture was dissolved by heating to 110° C. and 6.6 g of crotonaldehyde was added dropwise to the solution in 10 minutes. After 5 minutes, the reaction mixture was poured in 30 ml of ice water to give 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-nitroquinaldine, to which without isolation was added a solution of 71 g of stannous chloride dihydrate in 140 ml of concentrated hydrochloric acid and the mixture was stirred for 30 minutes. After treatment with activated carbon the reaction mixture was rendered alkaline with an aqueous sodium hydroxide solution to form precipitations which were extracted with dichloromethane. After distilling off the solvent isopropanol was added to the residue to dissolve it. Concentrated hydrochloric acid was added to the solution to form hydrochloric acid salt which was well washed with acetone and dissolved in water. The aqueous solution was rendered alkaline with an aqueous sodium hydroxide solution to precipitate solids which were collected by filtration to give 8.5 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-aminoquinaldine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4[CH2:22][O:21]4)[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][CH2:22][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[OH:21]
Reactant: Clc1ccc2ccc(/C=C/c3cccc(C4CO4)c3)nc2c1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1SCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a stirred solution of epoxide 30 (37 g, 0.120 mol) in a mixture of dimethylformamide (140 ml) and acetonitrile (200 ml) was added methyl-2-mercaptobenzoate (20.0 g, 0.145 mol), followed by addition of anhydrous potassium carbonate (19.8 g, 0.145 mol). The reaction mixture was stirred overnight, filtered and concentrated. The resulting mixture was poured into water (2.0 L), stirred and extracted with ethylacetate (1.0 L). The organic layer was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulphate, evaporated and subjected to FC (EtOAc/hexanes) to afford product as a pale yellow solid 46 (18.0 g, 31% yield).
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.F[C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(OCC)C.CN(C=O)C.CCOC(C)=O>[CH:1]1([S:4][C:6]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=2[CH:8]=[O:9])[CH2:3][CH2:2]1
Reactant: SC1CC1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Freshly prepared cyclopropyl thiol in THF/diethyl ether (J. Am. Chem. Soc. 1992, 114(9), 3497) was added to 2-fluoro-5-nitrobenzaldehyde (3.4 g, 20 mmol, 1.0 eq.) and K2CO3 (4.83 g, 35 mmol) in DMF (20 mL). The mixture was stirred at 45° C. for 1.0 h and at rt over night. It was diluted with EtOAc and washed with water. The aqueous was extracted with EtOAc and the combined organic layers were washed with brine and dried over Na2SO4. After evaporation of solvent, the crude was tritutated with EtOAc/hexanes (70/120). The solid was collected to give 76A (3.2 g). The filtrate was condensed and triturated again to give a second crop of 76A (0.5 g, total yield 85%). 1H NMR (400 MHz, CDCl3) δ ppm 0.74-0.83 (m, 2H) 1.20-1.28 (m, 2H) 2.13-2.19 (m, 1H) 7.95 (d, J=9.23 Hz, 1H) 8.33 (dd, J=8.79, 2.64 Hz, 1H) 8.62 (d, J=2.64 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:16][CH2:17][CH2:18]Cl)[C:13]([NH:14][CH3:15])=[C:9]2[C:8](=[O:20])[N:7]([CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[H-].[Na+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]3[CH2:16][CH2:17][CH2:18][N:14]([CH3:15])[C:13]3=[C:9]2[C:8](=[O:20])[N:7]([CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(NC)n(CCCCl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c3n(nc21)CCCN3C
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
To a stirred solution of 7-butyl-2-(3-chloropropyl)-3-methylamino-5-propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(2.0 g) in DMF(30 ml) was added sodium hydride(60% oil, 0.67 g), in portions under ice-cooling. The mixture was stirred at room temperature for further 5 hours. The reaction mixture was concentrated to dryness and the concentrate was added to ice-water. The mixture was stirred for a while, whereupon crystals precipitated out. The crystals were collected by filtration and recrystallized from isopropyl ether to afford colorless crystals(1.55 g, 90%), m.p. 94°-98° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([N:34]1[CH:11]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:19][CH2:20]2)=[O:14])[CH2:12][N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:35]1=[O:36])[CH:32]=[CH2:33]
Reactant: C=CCN=C=O
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: C=CCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and allyl isocyanate to give the title compound as a colorless solid. MS: 483.2 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH3:10][C:11]([OH:13])([CH3:14])[CH2:12][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: CC(C)(O)CCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
A mixture of 4-nitro-1H-pyrazole (1.6 g, 13.9 mmol), 1-chloro-2-methylpropan-2-ol (1.5 g, 13.9 mmol) and Cs2CO3 (9.1 g, 27.8 mmol) in DMF (20 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to RT and diluted with EA (200 ml). The organic phase was washed by water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow oil (2.0 g, 78%), which was used for the next step without further purification. MS (ES+) C7H11N3O3 requires: 185, found: 186 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1Br.[S:12]([O-])([O-])(=O)=O.[Na+].[Na+].[S].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:12]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(S)c(Cl)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-chloro-4-nitro-bromobenzene (20 g) was dissolved in ethanol (160 ml), and an aqueous solution of sodium sulfate nanohydrate (15.2 g) and sulfur (2.0 g) in ethanol (200 ml) was added dropwise to the solution for 20 minutes under heat reflux. An aqueous solution of sodium hydroxide (5.1 g, 20.3 ml) was added dropwise to the solution for 20 minutes, and then, the mixture was cooled to room temperature, and ice-water was added thereto. The precipitates were filtered, and the pH of the filtrate was adjusted to about pH 5 with 6N hydrochloric acid, and the precipitates were collected by filtration and washed with water to give 2-chloro-4-nitrobenzenethiol (9.4 g).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1ccc(C(=O)OC)cc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)n1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a solution of methyl 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylate (209 mg, 1 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added lithium hydroxide (120 mg, 5 mmol) in water (7 mL), then stirred at room temperature for 12 hour, the reaction mixture was concentrated, to the residue was added water (10 mL), acidified with hydrochloric acid to PH=4, collected and dried the solid to give 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (98 mg, 50%). LRMS (M+H+) m/z: calcd for 195.09. found 195.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:12])[S:5][C:6]=1[CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:4]1[S:5][C:6]([CH2:7][C:8]([Cl:11])([Cl:9])[Cl:10])=[C:2]([CH3:1])[N:3]=1)(=[O:24])=[O:23]
Reactant: Cc1nc(N)sc1CC(Cl)(Cl)Cl
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: Cc1nc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)sc1CC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 46 %

Procedure:
The title compound was prepared according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol, prepared according to Dodinov, A. A et al (1993) Chem. Heterocycl. Comp (Eng. Transl.) 29(8): 955-958) and 2,4,6-trichlorobenzenesulfonyl chloride (140 mg, 0.5 mmol). The solution was allowed to stand at room temperature overnight. The solution was directly loaded on a silica gel column for flash column chromatography, eluted with a mixed solvent of ethyl acetate and hexane (up to 40% v/v) to give a solid product. Crystallization of the product from ethyl acetate and hexane gave the title compound as a white solid (112 mg, 46% yield): mp 228-229° C.; MS m/e 487, 489, 491, 493; Anal. Calcd. (found) for C12H8Cl6N2O2S2: C 29.5 (29.7) % H 1.7 (2.1) % N 5.7 (5.8) %.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:32]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred 0° C. solution of 1-t-Butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine (3.0 g, 10 mmol) from Step 1 of Example 41 in dry THF (40 mL) was added DIEA (5.2 mL, 30 mmol), followed by triphosgene (1.08 g, 3.60 mmol). After 30 min, the reaction was warmed to ambient temperature and stirred for 24 h. The precipitated hydrochloride salt of DIEA was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (2×100 mL), water (100 mL), 5% aqueous citric acid (100 mL), and brine (100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. 3-(1-t-Butyloxycarbonyl-4-piperidinyl)benzoxazolidin-2-one was obtained as a solid (82% yield).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=2)[O:4][C:3]=1[C:23]1[CH:28]=[C:27]([O:29]C)[C:26]([O:31]CC2C=CC=CC=2)=[C:25]([O:39]C)[CH:24]=1.B(Br)(Br)Br.CO.O>ClCCl>[CH2:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][C:3]([C:23]1[CH:28]=[C:27]([OH:29])[C:26]([OH:31])=[C:25]([OH:39])[CH:24]=1)=[C:2]([OH:1])[C:11]2=[O:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCc1ccc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2oc(-c3cc(O)c(O)c(O)c3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 106.5 %

Procedure:
To a stirring solution of 3-hydroxy-6-decyl-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one (0.369 g, 0.7 mmol) in dichloromethane (20 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 3.4 ml, 3.4 mmol, 5 equ). The mixture was warmed to room temperature and then stirred for 15 hours. Methanol (10 ml) was then added. The reaction was heated to reflux for 1 hour, then concentrated in vacuo to give a brown solid. Water (25 ml) was added and then extracted into ethyl acetate (3×). The organic layer was washed with brine then dried (MgSO4) and concentrated in vacuo to give 11g (0.318 g, 110%) as a brown oil.
Reaction SMILES: [C:1]([C:3]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1Br)#[N:2].[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:32]1[CH:33]=[CH:34][S:30][CH:31]=1)#[N:2]
Reactant: CC(C#N)(COc1cc(F)c(F)cc1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C#N)(COc1cc(F)c(F)cc1-c1ccsc1)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
120 mg of N-[2-cyano-1-(2-bromo-4,5-difluorophenoxy)-2-propyl]-4-trifluoromethoxybenzamide, 160 mg of thiophene-3-boronic acid and 3 ml of saturated aqueous sodium bicarbonate solution are dissolved in 4 ml of toluene and degassed for 15 minutes using a stream of nitrogen. Subsequently, 9 mg of tetrakis(triphenylphosphine)palladium are added and the mixture is stirred at reflux for 20 h. The mixture is subsequently diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and evaporated. After purifying by means of HPLC, the title compound is obtained with a melting point of 128-30° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:43]([C:47]1[O:51][N:50]=[CH:49][C:48]=1[C:52](O)=[O:53])[CH2:44][CH2:45][CH3:46]>CN(C=O)C>[CH2:43]([C:47]1[O:51][N:50]=[CH:49][C:48]=1[C:52]([N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1)=[O:53])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCc1oncc1C(=O)O
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1oncc1C(=O)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-butylisoxazole-4-carboxylic acid (17 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C17H21N3O2: 299.1634, found 299.1635.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH2:3][CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.O[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:21][CH2:20][CH2:19][O:17][C:14]2[CH:15]=[CH:16][C:11]([CH:2]3[CH2:3][S:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1]3)=[CH:12][CH:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OCCCN1CCCC1
Reactant: Oc1ccc(C2CSc3ccccc3O2)cc1
Product: c1ccc2c(c1)OC(c1ccc(OCCCN3CCCC3)cc1)CS2

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(2,3-dihydro-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 2-4 and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[I-:17].[K+].II>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([I:17])[CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: O=C(c1ccc(O)cc1)c1cccc(F)c1
Agent: II
Agent: [K+]
Product: O=C(c1cccc(F)c1)c1ccc(O)c(I)c1

Procedure:
The product from Example 69A, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 6.92 (d, 1H, J=8.9 Hz), 7.31-7.59 (m, 4H), 7.67 (d, 1H, J=8.9 Hz), 8.18 (s, 1H); MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2C(OC(C)(C)C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>>[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16]([S:26]([CH3:28])=[O:27])=[CH:15][N:14]2[C:11]2[N:12]=[CH:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][N:10]=2)=[CH:18][CH:19]=1)=[O:25]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC4CC3CN4)ccc12

Procedure:
Prepared from 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in two steps comprising a T3P coupling and a TFA-catalyzed removal of the Boc protecting group. Light yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.CO.[OH-].[K+].Cl>C1COCC1>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(O)c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a solution of methyl 4-[hydroxy(phenyl)methyl]benzoate from step 1 (1.6 g, 6.6 mmol) in THF (40 mL) was added methanol (13 mL) and 1.0N aqueous potassium hydroxide solution (13.2 mL, 13.2 mmol). The mixture was heated at 70° C. for 20 minutes and then cooled down to room temperature. Methanol and THF were evaporated under reduced pressure. 3.0N hydrochloric acid (7.5 mL, 22.5 mmol) was added to the crude residue. The solid obtained was filtered to afford the title acid as a white solid. The resulting crude compound was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]([CH2:28][CH:29]=O)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]([CH2:28][CH2:29][N:33]1[CH2:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32]1)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:25])[O:23]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1Cc2ccccc2C1)N(C)C(=O)OC(C)(C)C

Procedure:
Ethyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(2-(isoindolin-2-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate was prepared in accordance with the procedure of step 6 in Example 27 except that ethyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate was used instead of 3-phenylpropanal and isoindoline was used instead of (R)-2-acetamido-2-((1s,3S)-3-aminocyclobutyl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide hydrochloride. Rf 0.32 (10% MeOH in dichloromethane). 1H NMR (CDCl3, 300 MHz) δ 7.20-7.14 (m, 4H), 4.13 (q, J=8.0 Hz, 2H), 3.96 (br s, 4H), 3.00-2.88 (m, 4H), 2.75-2.60 (m, 2H), 2.41-2.31 (m, 1H), 2.15-1.95 (m, 2H), 1.87-1.74 (m, 2H), 1.49-1.08 (m, 26H), 0.79 (t, J=8.5 Hz, 2H). ESI MS found for C30H49B1N2O6 m/z [545.6 (M+1)].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:10]1=2
Reactant: COc1ccc2c(c1)CCCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a methylene chloride (10 ml) solution of 6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Tetrahedron, 1994, 50, 3297) (2.28 g, 12.0 mmol) was added methylene chloride solution of boron tribromide (1M, 24 mL, 24.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was then quenched with methanol and then the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=⅓ to furnish 2.0 g (96% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[Cl:24][C:25](OC(Cl)(Cl)Cl)=[O:26]>C1COCC1>[O:12]=[C:9]1[N:8]([C:25]([Cl:24])=[O:26])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cl)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of (R)-(−)-4-phenyl-2-oxazolidinone in THF (200 mL) at 0° C. was slowly added a 2.5 M solution of butyllithium in hexane (19 mL, 0.03 mol). The mixture was stirred at 0° C. for 30 min and then cooled to −78° C. Trichloromethyl chloroformate (7.8 mL, 0.03 mol) was added quickly in one portion and the reaction solution was stirred at −78° C. for 30 min. The resulting mixture was allowed to warm to room temperature, and was subsequently concentrated in vacuo. The resulting residue was taken up in CH2Cl2 (200 mL) and filtered, and the filtrate was concentrated in vacuo to afford the title compound as an off-white solid (4.5 g, 65%).