Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:25]C=O)[CH:20]([NH:28][C:29](=[O:59])[C:30](=[N:56][O:57][CH3:58])[C:31]1[N:32]=[C:33]([NH:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[S:34][CH:35]=1)[C:19]2=[O:60])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:85]([Cl:87])[Cl:86]>C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:25][CH:85]([Cl:87])[Cl:86])[CH:20]([NH:28][C:29](=[O:59])[C:30](=[N:56][O:57][CH3:58])[C:31]1[N:32]=[C:33]([NH:36][C:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[S:34][CH:35]=1)[C:19]2=[O:60])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h

Procedure:
Following the procedure described in Example 11B, a solution of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-oxoethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 13c) (2.3 g) in methylene chloride (15 cc), cooled to -40° C., is treated with a 0.5 M solution (5.5 cc), in methylene chloride, of the addition compound of chlorine and triphenyl phosphite. The reaction mixture is stirred for 3 hours at a temperature between -40° C. and -20° C. and then diluted with ethyl acetate (200 cc). The organic solution is decanted and washed with a semisaturated solution of sodium bicarbonate and sodium chloride (50 cc) and then a saturated solution of sodium chloride (3×50 cc). The aqueous phases are reextracted with ethyl acetate (50 cc) and the combined organic solutions are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is stirred with isopropyl ether (150 cc) for 16 hours. The precipitate is filtered off, washed with isopropyl ether (50 cc) and then redissolved in methylene chloride (50 cc) and fixed to silica gel (0.2-0.06) (8 g), which is deposited on a column of silica gel (0.06-0.04) (diameter of the column: 1.8 cm; height: 35 cm). Elution is carried out with a mixture of cyclohexane and ethyl acetate (75/25 by volume) under a pressure of 80 kPa, 50 cc fractions being collected. Fractions 5 to 7, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. This yields the syn isomer of 2-benzhydryloxycarbonyl-3-(2,2-dichloroethyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 13d) (0.25 g) in the form of a whitish solid.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[SH2:29]>C(O)C>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[S:29])[NH2:2]
Reactant: S
Reactant: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1cccs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C(N)=S)c1cccs1
Yield: 88 %

Procedure:
0.72g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (12) was dissolved in 10ml of ethanol and then 0.63ml of triethylamine was added thereto. The reaction solution was stirred under reflux for 8 hours while introducing hydrogen sulfide gas. After removing the solvent, water was added to the residue and then the solid product which is not dissolved in water was filtered. The filtered solid product was washed with diethylether and then dried to obtain 0.70g (Yield 88%) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)cc3)n(C(C)(C)C)n2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n(C(C)(C)C)n2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Methanesulphonyl chloride (0.042 mL, 0.55 mmol) was added at 0° C. to a solution of N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide (0.231 g, 0.5 mmol) and N,N-diethylethanamine (0.077 mL, 0.55 mmol) in DCM (4 mL). The resulting solution was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate (10 ml) filtered and the solid washed with DCM (2×10 ml). The organic layers were combined and washed with water (20 ml) and saturated brine (20 ml). The organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide (0.255 g, 94%) as a white solid. MS: m/z=540 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyridine (90 mg, 0.33 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[F:12][C:13]([F:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH:14]=[N:15][C@H:16]([C:22]12[O:29][CH2:28][C:25]([CH3:30])([CH2:26][O:27]1)[CH2:24][O:23]2)[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CCOCC>[F:37][C:13]([F:12])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:14]([NH:15][C@H:16]([C:22]12[O:23][CH2:24][C:25]([CH3:30])([CH2:26][O:27]1)[CH2:28][O:29]2)[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1
Reactant: Brc1ccsc1
Reactant: CC(C)(C)C[C@H](N=CC(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)C[C@H](N[C@@H](c1ccsc1)C(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Temperature: -40 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
To a solution of 3-bromothiophene (597 mg, 6.3 mmol) in dry ether (10 ml) at −70° C. was added nBuLi (1.6 M, 2.5 ml) and the reaction mixture was stirred for 2 h at the same temperature. A solution of (2,2-difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (1.16 g, 3.15 mmol) (prepared as described in Example 9 above) in ether (5 ml) was added and stirring was continued while the reaction mixture was allowed to warm to −40° C. The reaction mixture was quenched with water and the organic layer was separated, washed with brine and dried over MgSO4. The crude product was purified by column chromatographed to give (2,2-difluoro-2-pyridin-2yl-1(S)-thiophen-3-ylethyl)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)butyl]amine (350 mg) which was converted to 2(S)-[2,2-difluoro-1(S)-(thiophen-3-yl)-2-pyridin-2-ylethylamino]-4,4-dimethylpentanoic acid as described in Example 9, Step 9 above and then converted to the title compound as described in Example 1, Step 12 above.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[CH3:12])[N:23]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CC1CCCN1c1cccc(N)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.3 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (0.84 g, 4.73 mmol), Pd2(dba)3 (0.247 g, 0.43 mmol), BINAP (0.536 g, 0.86 mmol) and Cs2CO3 (4.21 g, 12.9 mmol) in dioxane (30 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.2 g, 85%) as a yellow solid. LC-MS: [M+1]+=329, tR=1.930 min.
Reaction SMILES: C[O:2][CH2:3][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=O)=[CH:6][CH:5]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[CH3:12][O:11][CH2:9][C:7]1[O:8][C:4]([C:3]([NH:15][CH2:14][CH2:13][NH2:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COCc1ccc(C(=O)OC)o1
Reactant: NCCN
Product: COCc1ccc(C(=O)NCCN)o1

Procedure:
Using Compound c and anhydrous ethylenediamine, the corresponding procedure of Example 1 was repeated to give 5-(methoxymethyl)-N-(2-aminoethyl)-2-furancarboxamide (Compound d) as light yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.075 g, 0.746 mmol) obtained in step 4 and methanesulfonamide (0.071 g, 0.749 mmol), the title compound (0.026 g, 30%) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1.[N+](C)([O-])=O.[Br:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](Cl)=[O:24]>ClCCl>[Br:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[OH:6])=[O:24]
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: CCCCC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCCC(Br)C(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Aluminium chloride (20.00 g, 150 mmol) was carefully added to a stirred solution of N-(4-methoxyphenyl)acetamide [3a] (8.26 g, 50.0 mmol) in dichloromethane (30 mL) at 0-5° C. (ice/water bath). Nitromethane (8.2 mL, 150 mmol) was added to the mixture in one portion. A solution of 2-bromohexanoyl chloride (12.81 g, 60.0 mmol) in dichloromethane (20 mL) was added dropwise to the stirred mixture at room temperature. The obtained mixture was stirred for 4 hours at the same temperature. Aluminum chloride (6.67 g, 50.0 mmol) was added in one portion to the stirred mixture at room temperature. The mixture was stirred overnight at the same temperature. The mixture was carefully poured into ice/water mixture. The mixture was extracted with ethyl acetate (150 mL then 2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure at 50° C. (water bath). The residue (21.20 g) was stirred with hexane (150 mL) for 1 hour at room temperature. The precipitated solids were filtered off, washed on the filter with hexane and dried at 50° C. (water bath) to the constant weight to give 15.03 g (91.6%) of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] as yellow crystals with mp 137-138° C. (toluene).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[N:23]3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nccnc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoxaline-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 378.17 g/mol.
Reaction SMILES: FC1C=C(C=CC=1)CO[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[NH:12][CH2:11][CH2:10][C:9]=2[N:8]=1.C(Cl)Cl.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>CC([O-])=O.CC([O-])=O.[Cu+2].C(N(CC)CC)C>[F:24][C:25]1[CH:30]=[C:29]([N:12]2[CH2:11][CH2:10][C:9]3[N:8]=[CH:7][CH:16]=[CH:15][C:14]=3[C:13]2=[O:17])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2cccnc2CCN1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (30 mg, 0.11 mmol) was dissolved into DCM (2 mL) and treated with 3-fluorophenylboronic acid (30 mg, 0.22 mmol), Cu(OAc)2 (22 mg, 0.13 mmol), and triethylamine (50 μL). The reaction was stirred for 2 days at RT and concentrated to an oil and purified by RP-HPLC (10-90% gradient CH3CN in water with 0.1% TFA modifier) to give the compound, 24(3-fluorobenzyl)oxy)-6-(3-fluorophenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. LC-MS (M+H)=367.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CC([Mg]Cl)C.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH2:8][OH:9])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OCc1ccncc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OCc1ccncc1C1(O)CCN(Cc2ccccc2)CC1
Yield: 15.8 %

Procedure:
To a solution of 1.9 g (10 mmol) (3-bromo-pyridin-4-yl)-methanol in 50 ml dry tetrahydrofuran were added 11 ml (21 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was heated at reflux for 2 h. A solution of 1.9 g (10 mmol) 1-benzyl-4-piperidone in 5 ml tetrahydrofuran was added dropwise at a temperature of approximately 65° C. The reaction mixture was heated at reflux for 2 h and then quenched with water. The tetrahydrofuran was evaporated. The aqueous layer was basified to pH 10 with aqueous 2 M sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (0.47 g, 16%) as a brown solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)O
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
Anthranilic acid (274.3 g) and acetic anhydride (1.1 L) were combined then heated at reflux for 3.5 hours. The reaction mixture was concentrated under vacuum. The residue was combined with methanol (550 mL) then concentrated under vacuum to provide 2-methyl-4-oxo-3,1-benzoxazine as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Aldrich, 2.01 g, 10 mmol) in tetrahydrofura n (15 mL) at —78° C., n-BuLi (2.5 M in hexanes, 11 mmol, 4.4 mL) was added dropwise. After the addition, 4-fluoro nitrobenzene (1.41 g, 10 mmol) was added and the solution was gradually warmed to room temperature and stirred for 2 hours. The solution was poured into water and the mixture was extracted with ether. The extract was dried (Na2SO4) and concentrated to give the crude which was chromatographed (20% ethyl acetate/hexanes) to yield a pale yellow oil. 1.34 g.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=2[S:7][CH:6]=1)[CH3:4].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[CH:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[S:7][CH:6]=1)[CH3:4]
Reactant: CC(c1csc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(c1csc2c1OCCNC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
tert-Butyl 8-(2,2,2-trifluoro-1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (140 mg) was dissolved in ethyl acetate (2 mL), 4 N hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give the title compound (88.4 mg, 76.9%) as a solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1)=[O:6])=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1cccc(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: NCC(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Add palladium on carbon (720 mg, 10% Pd/C, 50% water by weight) to a nitrogen purged solution of 2-azido-1-(3-(trifluoromethoxy)phenyl)ethanone (1.70 g, 6.93 mmol) in ethanol (15 mL). Purge the flask with hydrogen (balloon). Stir at room temperature overnight. Filter the mixture over Celite®, rinse the Celite® with ethanol (3×30 mL), and concentrate the filtrate in vacuo to provide crude 2-amino-1-(3-(trifluoromethoxy)phenyl)ethanone (1.56 g, 88%). 1H NMR (DMSO-d6) δ 8.56 (br s, 2H), 8.07 (m, 1H), 7.95 (s, 1H), 7.76 (m, 2H), 4.63 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CNN.C(OCC)C>ClCCl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: ClCCl
Solvent: CCOCC
Product: CN(CCON)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.3 %

Procedure:
A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2H), 2.86 br s, 3H), 1.25 (br s, 9H); MS (APCI+)=191.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (5.1 g, 30 mmol) and N-bromosuccinimide (6.2 g, 36 mmol) in acetonitrile (50 mL) was heated at reflux for overnight. It was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous K2CO3 solution (100 mL×2). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109a as a yellow solid (8.1 g, 100%). LCMS: [M+H]+ 253. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 6.64 (s, 2H).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:33]=[C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:32])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(4-ethylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 12, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.