Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:16]=[C:15]([C:24](O)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccncc2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccncc3)n2)CN1

Procedure:
22 mg (0.05 mmol) of the compound of Example 45A is reacted analogously to the synthesis of the compound of Example 1 with 7 mg (0.06 mmol) of 4-imidazolinone-hydrochloride. 24 mg (94% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(N(CC)CC)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>CN(C)C=O>[C:29]1([S:35]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]([NH:9][CH2:8][CH2:7][O:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:11])[CH2:18][CH2:17]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(S(=O)(=O)c3ccccc3)CC2)c1
Reaction time: 13 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide. 0.2 ml (1.43 mmol) of triethylamine and 253 mg (1.43 mmol) of benzenesulfonyl chloride were added to the solution at 0° C., and they were stirred for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.09, m/z=450; 1H NMR (CDCl3) 1.26-1.39 (m, 1H), 1.50 (d, 3H), 1.59-1.70 (m, 1H), 1.81-1.99 (m, 3H), 2.09-2.20 (m, 2H), 2.22-2.34 (m, 1H), 2.71 (s, 3H), 2.90 (m, 1H), 3.50 (t, 2H), 5.67 (m, 1H), 6.90-7.08 (m, 4H), 7.19 (m, 1H), 7.21 (m, 1H), 7.33 (d, 1H), 7.62 (d, 1H), 7.77 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH:21]=O)[CH3:19].C(OC(OCC)CN(C)C)C.[BH4-].[Na+]>O.C(O)C>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC=O
Reactant: Nc1cccc(-c2nc3ncccc3o2)c1
Agent: CCOC(CN(C)C)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CCNc1cccc(-c2nc3ncccc3o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.1 g., (0.005 mole) of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine and 50 ml. of ethanol is reacted with dimethylaminoacetaldehyde [from 0.96 g. (0.006 mole) dimethylaminoacetaldehyde diethylacetal]by gentle heating to complete the intermediate Schiff base formation. The mixture is then cooled and 60 mg., (0.0015 mole) of sodium borohydride is added, and the mixture allowed to stir overnight at room temperature. Water is added, the solvents are removed in vacuo, and the residue is distributed between water and methylene chloride. The organic layer is dried and concentrated in vacuo to give crude 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine, purified via column chromatography using an alumina column with an ethylacetate-ether mixture (v/v 0-60% ethylacetate) as eluant.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1)[CH:2]=C.C[N+]1([O-])CC[O:30]CC1.O1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[O:30]=[CH:2][CH2:1][C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cn(S(=O)(=O)c2ccccc2)c2cccc(C(=O)OC)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2c1c(CC=O)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a 0° C. cooled solution of methyl 3-allyl-1-(phenylsulfonyl)-1H-indole-4-carboxylate (4.80 g, 13.50 mmol) from Step B above and N-methylmorpholine-N-oxide (2.82 g, 24.31 mmol) in a 3:1 mixture of tetrahydrofuran/water (50 mL) was added OsO4 (4 wt % in water, 5.0 mL, 54.0 mmol). The resulting mixture stirred at room temperature for 24 h, then was diluted with a saturated aqueous solution of Na2S2O5 (200 mL). The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in a 3:1 mixture of tetrahydrofuran:water (50 mL), to which sodium periodate (11.55 g, 54.0 mmol) was added. The mixture stirred at room temperature for an additional 24 h. The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-(2-oxoethyl)-1-(phenylsulfonyl)-1H-indole-4-carboxylate (2.50 g, 45%) as a crude yellow oil, which was directly elaborated without purification.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C@:13]1([CH3:24])[CH2:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C:15]([NH2:23])=[N:14]1.FC(F)(F)C(O)=O>C(O)(=O)C.[Zn]>[NH2:10][C:6]1[CH:7]=[C:8]([F:9])[C:3]([Cl:2])=[C:4]([C@:13]2([CH3:24])[CH2:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C:15]([NH2:23])=[N:14]2)[CH:5]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cc(N)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
To a cooled (cold water) solution of (4S,6S)-4-(2-chloro-3-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.2 g, 3.37 mmol) in acetic acid (14 mL) was added 2,2,2-trifluoroacetic acid (2.00 mL, 27.0 mmol) followed by zinc, dust (1.19 g, 18.22 mmol) in one portion (exothermic). After stirred for 10 min, water bath was removed. The mixture was stirred at ambient temperature for 1.5 hrs and then concentrated. The residue was basified with 1N NaOH. The aqueous layer was extracted three times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (2-10% MeOH-DCM) to give (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as an off-white solid (0.636 g, 57.9% yield). MS m/z=326 [M+H]+. Calculated for C12H12ClF4N3O: 325.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:14]([CH3:16])[CH3:15].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:16])[CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxybenzoate (15.0 g, 64.9 mmol), 2-bromopropane (7.68 mL, 77.9 mmol) and potassium iodide (1.0 g, 6.49 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure. Brine was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (14.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][C:16]=1[O:22][CH3:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:19]2[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([Cl:14])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1Cl
Temperature: 100 °C
Yield: 77.9 %

Procedure:
To a 5 ml of toluene solution containing 0.20 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.1 mmol) and 0.238 g of 2-chloro-3-bromoanisole (1.1 mmol) were added 67.0 mg of BINAP (0.11 mmol), 24 mg of tris(dibenzylideneacetone)dipalladium (0.027 mmol) and 144 mg of sodium tert-butoxide (1.5 mmol). The mixture was heated under reflux under a nitrogen atmosphere at 100° C. for one hour. After cooling to room temperature, the reaction solution was filtered using Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→3:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.28 g of light yellow amorphous solid 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:27][CH3:28])[CH2:18]1)(C)(C)C>Cl.O1CCOCC1>[CH2:27]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:17]([CH2:16][O:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH2:7])[CH2:18]1)[CH3:28]
Reactant: CCN1CC(COc2ccc(C)cc2NC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CC(COc2ccc(C)cc2N)Cc2ccccc21

Procedure:
A solution of [2-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-3-ylmethoxy)-5-methyl-phenyl]-carbamic acid tert-butyl ester (40 mg, 0.1 mmol) was stirred in 4N HCl in dioxane (2 mL) at room temperature under a drying tube overnight. The suspension was concentrated by rotovap, diluted to 30 mL with CH2Cl2 and shaken with 10% Na2CO3 (30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated to a brown oil, which was used without purification in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[C:31]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([NH:39][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[CH:40][CH:41]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(C)(C)C)cc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 40.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 4-tert-butylaniline (0.079 g, 0.400 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.055 g of the desired product. 1HNMR (DMSO-d6): δ 1.21 (s, 9H), 1.55 (s, 6H), 3.13 (s, 2H), 7.27-7.46 (m, 6H), 7.55 (d, J=8.7 Hz, 2H), 9.67 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 507.50.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH2:11][C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: CCOC(=O)C1(CO)CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(COc2cc(C)c(Br)cn2)CCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In tetrahydrofuran (11 mL) were dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine (1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) was added dropwise to the solution at room temperature, and then, the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-])=O.BrC1[CH:21]=[C:20](C(F)(F)F)[N:19]=[C:18](C)[CH:17]=1>>[F:12][C:11]([F:14])([F:13])[C:6]1[CH:5]=[C:4]([N:1]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][N:7]=1
Reactant: Cc1cc(Br)cc(C(F)(F)F)n1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(N2CCNCC2)ccn1

Procedure:
The compound can be prepared from 4-Nitro-2-trifluoromethyl-pyridine 1-oxide [147149-97-1] in analogy to the procedure used for the preparation of 4-Bromo-2-methyl-6-trifluoromethyl-pyridine [615579-78-1] (WO03087056). MS (m/e): 227 (M+H+, 100%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1/[CH:17]=[CH:18]\[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][C@H:12]1/[CH:17]=[CH:18]\[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1/C=C\c1cccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](/C=C\c2cccnc2)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (5.2 g) in a mixture of ethyl acetate (50 ml) and triethylamine (2.90 ml) was added dropwise methanesulfonyl chloride (1.24 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (50 ml) and water (30 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of n-hexane and ethyl acetate (1:2, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (4.14 g).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH:13](C(O)=O)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:26]=1.[K].[OH-].[K+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:26]=1
Reactant: O=C(O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Yield: 80 %

Procedure:
Acetic acid is added to a solution of 0.409 g. (0.001 moles) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid, monopotassium salt, potassium hydroxide (4306 CB) in 4 ml. of distilled water to adjust the solution to pH 4. The solution is heated on a water bath for 15 minutes; a solid precipitates which is separated, washed with water and dried; weight 0.216 g; m.p. 214°-216°C; yield 80%. This product is identical with the product obtained in Example 14.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:39][C:40]([CH3:43])([CH3:42])[CH2:41][O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)CBr
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 100 °C

Procedure:
A glass vial was charged with 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared as described in Example 3; 159 mg, 459 μmol), tetrabutylammonium iodide (84.8 mg, 230 μmol), cesium carbonate (374 mg, 1148 μmol), DMF (1.8 mL), and 1-bromo-2,2-dimethylpropane (175 μl, 1377 μmol). The vial was sealed and heated in a Biotage Initiator microwave reactor for 2 h at 100° C. Additional portions of tetrabutylammonium iodide (85 mg), cesium carbonate (180 mg), and 1-bromo-2,2-dimethylpropane (100 uL) were added. The vial was again heated in the microwave for 2 h at 100° C. The mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel (eluting with 0-80% of a 90:10:1 DCM/MeOH/NH4OH mixture in DCM) to give 2′-(2,2-dimethylpropoxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine of a pale orange glass that solidified into an off-white solid. MS m/z=417.2 [M+H]+. Calc'd for C24H25N4O3: 417.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[IH:10].OO>O>[Cl:1][C:2]1[C:3]([I:10])=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: I
Agent: OO
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1I
Reaction time: 8 h

Procedure:
To a stirred suspension of 3,4-dichloroaniline (20 g, 123 mmol), HI (48%, 15.7 g, 123 mmol), H2O2 (30%, 8.3 g, 246 mmol) in H2O (62 mL) at r.t. The reaction mixture was stirred in dark at r.t for overnight. The supernatant was discarded, diluted with ethyl acetate:hexanes (1:10), quenched with saturates NaHSO3, stirred for 1 h at ambient temperature, filtered the solids. The filtrate was washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to get 1:4 regioisomeric mixture of iodo derivative (minor isomer is required). It was recrystallized from cyclohexane to afford 1:1 mixture of regioisomers enriched in the filtrate. This mixture was further purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexanes (0-2%) to get the required compound as a cream color solid (5.2 g, ˜15% yield). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 4.32 (br, 2H).
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.Cl>O>[OH:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]([CH2:6][C:7]([OH:16])=[O:1])=[CH:4][O:8][C:9]=2[CH:10]=1
Reactant: [OH-]
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1coc2cc(O)ccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Sodium hydroxide (135 g) was dissolved in water (830 mL) to prepare a 14% aqueous sodium hydroxide solution. To a solution (623 mL) of 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (254 g) in water was added the above-mentioned 14% aqueous sodium hydroxide solution at 5° C., and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 4 hr. The concentrated hydrochloric acid (270 mL) was added at 35° C., a seed crystal was added, and the reaction mixture was stirred at 35° C. for 1 hr and at 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with water (123 mL), and dried at 60° C. under reduced pressure. To the crystals was added ethyl acetate (1.9 L), and the mixture was stirred at room temperature for 1 hr. After filtration, the insoluble material was washed with ethyl acetate (144 mL). To the filtrate was added activated carbon (16.5 g), and the mixture was stirred at 25° C. for 1 hr and filtered again. The filtrate was concentrated and dried under reduced pressure to give (6-hydroxy-1-benzofuran-3-yl)acetic acid (146 g). (6-Hydroxy-1-benzofuran-3-yl)acetic acid (130 g) was dissolved in methanol (270 mL), a solution of (1R)-1-phenylethylamine (82 g) in methanol (90 mL) was added at 60° C., and diisopropyl ether (3.6 L) was added at 55° C. After stirring at 25° C. for 2 hr, the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (445 mL) of methanol-diisopropyl ether (1:9), and dried at 50° C. under reduced pressure to give the title compound (198 g) as white crystals.