Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(N(CCC)CCC)CC>>[Cl:21][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Agent: CCCN(CCC)CCC
Product: Cc1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 115 °C
Yield: 84.1 %

Procedure:
A solution of 6-methyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (10.7 g, 41.9 mmol) in phosphorous oxychloride (39 mL, 419 mmol) was treated with tri-n-propylamine (16 mL, 83.9 mmol) and refluxed at 110-120° C. for 1 hours. The solvent was evaporated, azeotroped three times with toluene, then dried in vacuo. The residue was taken up in ethyl acetate, washed sequentially with 1 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (1:9)] provided the title compound (9.61 g, 84% yield) as an orange oil. 1H NMR (CDCl3, 500 MHz) δ 2.63 (3H, s), 7.26 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H) ppm; MS (FIA) 273.0 (M+H); Rt (Method A) 3.499 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([NH2:24])=O)[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]#[N:24])[CH:15]=1
Reactant: CCCn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide (16.3 g, 50.0 mmol) and pyridine (20.9 mL, 150 mmol) in dichloromethane (100 mL) at 0° C. was added a solution of trifluoroacetic anhydride (9.89 mL, 70.0 mmol) in dichloromethane (100 mL) over ten minutes. The solution was stirred at 0° C. for about 15 minutes, then was allowed to warm to ambient temperature. After 45 minutes, saturated aqueous sodium bicarbonate (200 mL) was added and the dichloromethane was removed under reduced pressure. A white solid was isolated by filtration, washed with water, and dried. The solid was recrystallized from 1:1 heptane/ethyl acetate to yield 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][B:19](/[CH:2]=[CH:1]/[C:3]2[CH:15]=[CH:14][C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][CH:4]=2)[O:18]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#Cc1ccc(CN2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 4-(4-ethynylbenzyl)morpholine (120 mg, 0.596 mmol), toluene (2.5 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 mL, 2.98 mmol). The mixture was stirred for 15 min while purging the solution with N2 (g). HRuCl(CO)(PPh3)3 (29 mg, 0.030 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (2×) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 2:3 to 1:2) to give a white solid (155 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=18.8 Hz), 7.30 (m, 2H), 6.15 (d, 1H, J=18.5 Hz), 3.72 (bs, 4H), 3.49 (bs, 2H), 2.45 (bs, 4H), 1.31 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.22.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1)[CH3:13].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:12]([C:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1)(=[O:11])[CH3:13]
Reactant: CC(O)C1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A precooled (−78° C.) solution of oxalyl chloride (2.82 mL, 32.4 mmol) in 150 mL of DCM was treated dropwise with a solution of DMSO (4.60 mL, 64.8 mmol) in 25 mL of DCM. After an additional 5 min, a solution of 3-(1-hydroxyethyl)-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanol (4.33 g, 10.8 mmol) in 25 mL of DCM was added dropwise. The reaction mixture was stirred for an additional 30 min, then neat triethylamine (18.1 mL, 130 mmol) was added dropwise. The mixture was stirred for an additional 10 min, then was warmed to rt and stirred for 1.5 h. The reaction mixture was poured into 1N HCl solution and the resulting mixture was extracted with DCM. The organic layer was washed again with 1N HCl solution, then with saturated NaHCO3 solution, and finally with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 75% ethyl acetate/hexanes) gave 3-acetyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanone as a mixture of two enantiomers. ESI-MS calc. for C17H16F3NO4: 355; Found: 356 (M+).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2].C(O)(=O)C.O>C(O)C.[Fe]>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cnc(NC(=O)Nc2cccc([N+](=O)[O-])c2)s1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cnc(NC(=O)Nc2cccc(N)c2)s1
Yield: 60.2 %

Procedure:
A mixture of 1.55 g (5.05 mmol) of (5-isopropyl-1,3-thiazol-2-yl)-N′-(3-nitrophenyl)urea prepared as described in example 5 and 0.98 g ((17.7 mmol) of iron dust with 2.02 ml (35.35 mmol) of glacial acetic acid in 50 ml of ethanol was stirred at reflux under argon atmosphere. After 5 hours 1.5 l of water was added and the product extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was finally purified by chromatography on a silica gel column (chloroform/methanol 47/3) giving 0.84 g of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C@@H:9]1[O:11][CH2:10]1)Cl.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13]>CC#N>[O:11]1[CH2:10][C@H:9]1[CH2:7][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: ClC[C@H]1CO1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OC[C@@H]2CO2)cc1
Yield: 90 %

Procedure:
Potassium carbonate (414 g) and (R)-(−)-epichlorohydrin (800 mL) were added to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under an inert atmosphere for 2 h. The hot solution was filtered and the filtrate concentrated, giving a clear oil which was crystallised from di-iso-propyl ether giving the product in 90% yield.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:16])[N:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:9]1=O>C1COCC1>[CH3:14][N:13]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1([CH3:16])[CH3:7]
Reactant: CN1CCNC(=O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNCC1(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiAlH4 (1M in THF, 47 mL, 47 mmol, 1.5 equiv) was added to a solution of 3,3,4-trimethyl-piperazin-2-one (Step 107.3) (4.5 g, 32 mmol) in THF (50 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 2 h at 50° C., quenched by addition of acetone, filtered through a pad of celite and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 1.9 g of the title compound as a yellow oil. Title compound: ESI-MS: 129.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:51][CH2:50][N:49]([CH3:52])[C:48](=[O:53])[CH2:47]4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=O)(C)(C)C>CO.Br.CC(O)=O>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([N:46]1[CH2:51][CH2:50][N:49]([CH3:52])[C:48](=[O:53])[CH2:47]1)[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.005 g, 0.007 mmol) in 1 mL of MeOH and 2 mL of 33% HBr in AcOH was stirred at room temperature for 2 h. The mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in 4 mL of MeOH and treated with 0.5 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N8O2 [M+H]+: m/z=489.3. found: 489.3.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C@@H:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[C@@H:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Brc1ccc(O[C@H]2CN3CCC2CC3)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 9B (282 mg, 1 mmol) was treated with N,N-dimethyl-4-amino-phenyl boronic acid (230 mg, 1.4 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.2) as a solid (118 mg, yield, 37%). 1H NMR (MeOH-d4, 300 MHz) δ 1.41-1.56 (m, 1H), 1.61-1.88 (m, 2H), 1.98-2.12 (m, 1H), 2.14-2.22 (m, 1H), 2.72-3.01 (m, 11H), 3.22-3.34 (m, 1H), 4.48-4.57 (m, 1H), 6.83 (dt, J=8.8, 3.0 Hz, 2H), 6.92 (dt, J=8.8, 2.1 Hz, 2H), 7.39-7.49 (m, 4H) ppm. MS (DCl/NH3) m/z 323 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=[S:14])=[S:13].[CH3:15]CN(CC)CC.IC.Cl>O1CCOCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:12]([S:14][CH3:15])=[S:13])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: Cl
Solvent: CI
Solvent: C1COCCO1
Product: CSC(=S)Nc1ccc(C)cc1C(=O)O
Temperature: 5 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of 2-amino-5-methylbenzoic acid (2.52 g, 16.7 mmol) and carbon disulfide (2.01 mL, 33.9 mmol) in 45 mL of dry 1,4-dioxane was added NEt3 (5.58 mL, 40.0 mmol) and the mixture were stirred under N2 atmosphere at 5° C. for 18 hours. Iodomethane (1.14 mL, 18.4 mmol) was added dropwise and the mixture was stirred as 5° C. for 1 hour. The reaction was poured into 25 mL of an aqueous solution of HCl (1M) and the mixture was concentrated to half its volume under reduced pressure and extracted three times with 75 mL of EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from chloroform to give 3 as a yellow solid (3.25 g, 81%). mp: 199° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[NH:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[CH2:41]([O:40][C:38]([C:36]1[NH:37][C:33]([NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)=[O:39])[CH3:42]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1ccc(N)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.428 mmol), ethyl 5-amino-1H-pyrrole-2-carboxylate (180 mg, 1.17 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 200 mg, 0.526 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (4 mL) and THF (4 mL) was stirred at 25° C. for 16 hours. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (20%-95% of acetonitrile/water) to afford chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-1H-pyrrole-2-carboxylic acid ethyl ester (42 mg, 16.3%) as an off-white powder. HRMS (ES) m/z Calcd for C30H30Cl2F2N4O3+H [(M+H)+]: 603 736. found: 603.1736.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28](=[O:34])[C:29](OCC)=[O:30])[CH3:26].CC([O-])(C)C.[K+].C(O)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:34])=[O:30])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-(3-methyl-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 1, 41.9 g, 1.0 eq.) and diethyloxalate (18.77 mL, 1.1 eq.) in tetrahydrofuran (241.7 mL) was dropped into a cold (0-5° C.) solution of potassium tert-butylate (28.54 g, 2.0 eq.) and ethanol (43.64 mL, 6.0 eq.) in tetrahydrofuran (1.022 L). The mixture was stirred for 3 h at 0-5° C. and for 18.5 h at room temperature, poured into 1M hydrochloric acid solution. The aqueous phase was extracted 3 times with tert-butylmethylether and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, evaporated to dryness in vacuo and crystallized from ethanol to yield 44.09 g (81%) as white crystals. MS (m/e): 436.2 (M, 5%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][C:12]=3[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[N:13]=[CH:14][O:15][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: NCCN1CCOCC1
Reactant: Fc1ccc(-c2ncoc2-c2ccc3nc(Br)sc3c2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ncoc2-c2ccc3nc(NCCN4CCOCC4)sc3c2)cc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 2-bromo-6-(4-(4-fluorophenyl)oxazol-5-yl)benzo[d]thiazole (0.030 g, 0.080 mmol, 1.0 eq.) and 4-(2-aminoethyl)morpholine (0.073 mL, 0.556 mmol, 7.0 eq.) in THF (1.5 mL) was mechanically shaken at 54° C. overnight. After cooling to room temperature, the solution was concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(4-(4-fluorophenyl)oxazol-5-yl)-N-(2-morpholinoethyl)benzo[d]thiazol-2-amine as a light yellow solid (0.0182 g, 54% yield). LC/MS (MH)=425.17.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=O.[I:20][C:21]1[CH:22]=[C:23]([CH2:27]C#N)[CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>CO>[I:20][C:21]1[CH:22]=[C:23]([C:27]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([C:15]5[S:16][CH:17]=[CH:18][CH:19]=5)[O:14][CH2:13][CH2:12][O:11]4)=[CH:6][C:5]=23)[CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(C2(c3cccs3)OCCO2)cc1
Reactant: N#CCc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Ic1cccc(-c2onc3ccc(C4(c5cccs5)OCCO4)cc23)c1

Procedure:
If one were to take 10 mmole of the dioxolane from Step A and treat it with 1.5 equivalents of (3-iodophenyl)acetonitrile and 5 equivalents of sodium hydroxide in anhydrous methanol and then refluxed the resulting reaction mixture for 2-3 hours, one would obtain after aqueous work-up the resulting 3-(3-iodo-phenyl)-5-(2-thiophen-2-yl-[1,3]dioxolan-2-yl)-benzo[c]isoxazole (3).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH2:36])=[S:35]>>[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:36][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:35]
Reactant: Cc1ccccc1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: Cc1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(o-tolyl)thiourea and isolated as an off-white solid (0.148 g, 37%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]=O.[H][H]>[Pd].C(OCC)(=O)C>[CH3:12][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=O
Reactant: COC(=O)c1ccccc1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1ccccc1C(=O)OC
Temperature: 5 °C

Procedure:
In a 5 gallon Star autoclave was placed methyl anthranilate (6.65 lbs, 20 mol), ethyl acetate (7000 mL) and K-10 powder (300 g). The mixture was cooled to 5° C. Then a 37% aqueous formaldehyde solution (1,600 mL, 21.2 mol) and 5% palladium on carbon catalyst (300 g) were added. The mixture was then hydrogenated at room temperature for 20 hours at an initial hydrogen pressure of 150 psi with continuous stirring. The mixture was filtered, and the solvent was evaporated at reduced pressure. The residue was distilled through a packed column (24×2") to provide methyl N-methylanthranilate b2.0 110° C. as a colorless liquid. Yield: 7.02 lbs (96.5% of theor.). GLC purity: 99%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:31])[C:6]([CH3:8])=[CH2:7])=[O:4].C1OC1C.[Br:36]N1C(=O)CCC1=O.ClCCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:31])[C:6]([CH2:8][Br:36])=[CH2:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC1CO1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 76 °C

Procedure:
A mixture of 4.45 g (10 mmoles) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one, 10 ml of propylene oxide, 3.6 g (20 mmoles) of N-bromosuccinimide, 50 mg of azo-isobutyronitrile, 100 ml of 1,2dichloroethane and 200 ml of carbon tetrachloride was heated for 5 hours at 76° C under nitrogen. After washing with sodium metabisulfite and water, the reaction mixture was concentrated and purified by column chromatography [silica gel; toluene-ethyl acetate 3:1 (v/v)] to obtain 1-(1-methoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one. The structure was confirmed by PMR and IR spectroscopy.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH:22]=[CH2:23])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:21]([CH:9]1[CH2:10][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][NH:8]1)[CH:22]=[CH2:23]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CC(OCc2ccccc2)CN1
Reaction time: 1 h

Procedure:
2-Allyl-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester, 51, (0.76 g, 2.4 mmol) is dissolved in methylene chloride (33 mL), and trifluoroacetic acid (25 mL) is added. The reaction mixture is stirred for 1 hour and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.