Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C[O:33]CC1>CCCCCC>[OH:33][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 118 ul (0.833 mmol) diisopropylamine in 3 ml THF were added 520 ul (0.833 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 150 mg (0.641 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.9, step 1) in 1.5 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 517 mg (1.282 mmol) (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) were added portionwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 1 hour at 0° C., the mixture was quenched with 2.5 ml of a saturated solution of sodium sulfite. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 82 mg (51%) of the title compound as a light brown oil. MS (m/e): 251.1 (MH+).
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[C:9]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25])=[S:14])(=O)[CH3:10].BrCC([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O>O>[CH3:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:13]1[S:14][CH:10]=[C:9]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:12]=1
Reactant: CC(=O)NC(=S)Nc1cc([N+](=O)[O-])ccc1C
Reactant: O=C(CBr)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Temperature: 27.5 °C

Procedure:
In a reactor, introduce methanol (1120 L), potassium carbonate (287 kg, 2076.70 mol) and 1-acetyl-3-(2-methyl-5-nitro-phenyl)-thiourea (67 kg, 264.53 mol). 2-bromo-1-pyridin-3-yl-ethanone (Int4) (52 kg, 259.96 mol) was then added and temperature maintained at 25-30° C. for 4 hours. Water (692 L) was added to the reaction mixture and precipitate filtered, washed with water and diisopropylether. The product was then dried in a tray drier at 45-50° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:25])[C:14]2=[O:24])=[CH:19][CH:18]=1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.56 g), 1-bromo-2-chloroethane (0.7 ml) and potassium carbonate (2.32 g) were stirred in DMF (20 ml) at 50° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated to give 3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a cream coloured solid (0.57 g); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.86 (m, 1H), 4.00 (t, 2H), 4.40 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.47 (d, 1H), 7.49 (d, 1H), 7.68 (s, 1H), 7.73 (m, 2H), 7.88 (d, 1H), 8.44 (d, 1H); Mass Spectrum: M+Na+ 419.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:30])=[CH:3][CH:4]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CNc1ccc(CCN(C[C@H](O)c2cccc(Cl)c2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of tert-butyl [2-(4-aminophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (1.75 g) and formaldehyde (37% w/w solution in water, 390 μl) in 1,2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23 g), and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was poured into a mixture of 1N sodium hydroxide and chloroform, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(methylamino)phenyl]ethyl]carbamate (550 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:19][N:20]([CH3:25])[S:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
To 6.8 g (0.04 mole) 2-hydroxybenzenesulfonamide in 100 ml methylene chloride was added 4.4 g (0.044 mole) triethylamine and 6.3 g (0.044 mole) dimethylsulfamoyl chloride in 5 ml methylene chloride, keeping the reaction temperature <10° C. The mixture was then warmed to room temperature and stirred 72 hours. The reaction mixture was then diluted with 100 ml methylene chloride washed with 100 ml water, 100 ml 1% HCl and dried over MgSO4. The solvent was evaporated to give a crude yellow oil that slowly solidified on standing. The solids were then triturated with hexanes and filtered to give 6.1 g of a tan solid, m.p. 88°-89° C.
Reaction SMILES: C(O[C:4](=[O:8])[C:5]#[C:6][CH3:7])C.[CH3:9][CH:10]([NH:18][NH2:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1>C(O)CCC>[CH3:7][C:6]1[NH:19][N:18]([CH:10]([CH3:9])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:8])[CH:5]=1
Reactant: CC(NN)c1ccc(F)cc1
Reactant: CC#CC(=O)OCC
Solvent: CCCCO
Product: Cc1cc(=O)n(C(C)c2ccc(F)cc2)[nH]1

Procedure:
8.3 g (0.074 mol) of tetrolic acid ethyl ester and 11.3 g of α-methyl-4-fluorobenzylhydrazine in 70 ml of n-butanol were heated for 8 hours under reflux.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:13]([O-])=O)[S:12][C:6]=2[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4]1.[C:22](O)(=[O:24])[CH3:23]>[Pd].C(OC(=O)C)(=O)C>[C:22]([NH:13][C:11]1[S:12][C:6]2[CH:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][N:3]([CH3:2])[CH2:9][CH2:8][C:7]=2[CH:10]=1)(=[O:24])[CH3:23]
Reactant: CN1CCc2cc([N+](=O)[O-])sc2C(c2ccccc2)C1
Reactant: CC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(s1)C(c1ccccc1)CN(C)CC2
Reaction time: 24 h

Procedure:
A suspension of 6-methyl-2-nitro-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrochloride (0.20 g) and 10% palladium on carbon (20 mg) in acetic acid (18 ml), acetic anhydride (2 ml) was hydrogenated on a Parr apparatus for 24 hours at 70 psi. The mixture was filtered and the filtrate evaporated. The residue was dissolved in water (30 ml), basified to pH~11 with ammonia solution and extracted with dichloromethane (2×50 ml). The extracts were dried filtered and evaporated to a yellow viscous oil. Crystallisation from toluene gave the title product (m.p. 180°).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([C:10]([CH:29]=[O:30])=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1Cc2cc3cc[nH]c3cc2C1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1Cc2cc3[nH]cc(C=O)c3cc2C1
Temperature: 50 °C
Yield: 30 %

Procedure:
A solution of dipropyl-(1,5,6,7-tetrahydro-1-aza-s-indacen-6-yl)amine (100 mg, 0.39 mmol) in dimethyl formamide (5 mL) was added to a solution of phosphorous oxychloride (200 μL, 329 mg, 2.14 mmol) in dimethyl formamide (5 mL) at -5° C. The mixture was heated at 50° C for 2 hours, poured on ice and treated with 5M sodium hydroxide and heated again for 20 minutes. After cooling, the mixture was extracted using dichloromethane. The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to yield a residue of 70 mg, which was purified on silica using methanol as eluant, yielding 33 mg (30%) of the pure compound as an oil.:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#Cc1ccc(OC2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: FC(F)(F)c1ccc(C#Cc2ccc(OC3CCCCO3)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3 (12.1 g, 60 mmol) and 4-bromobenzotriflouride (14.85 g, 66 mmol) in diisopropylamine (250 ml) was heated to 30° C. under nitrogen, and the solution was degassed. Then Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) and copper(I) iodide (114 mg, 0.6 mmol) were added to this clear solution. The reaction mixture was stirred for 2 hours at 80° C., then cooled to room temperature. The salt formed during the reaction procedure was filtered off and washed well with ethyl acetate. The filtrate was evaporated to dryness and hydrolyzed with concentrated hydrochloric acid (10 ml), water (100 ml) and crushed ice (50 g), then extracted with ethyl acetate. The combined organic paste was washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether-ethyl acetate=9:1) to give a pale yellow crystals of 4. Yield 16.6 g (80%); mp 112˜113° C.; δH(CDCl3; 300 MHz): 7.59(s, 4H, Ar—H), 7.48(d, J=8.7, 2H, Ar—H), 7.04(d, J=8.7, 2H, Ar—H), 5.46(t, J=3.1, 1H, OCHO), 3.89(m, 1H, THP), 3.62(m, 1H, THP), 1.86˜1.62(m, 6H, THP).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[OH:11])=O)=[CH:4][CH:3]=1.[CH:19]([NH2:21])=O.P(Cl)(Cl)(Cl)=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:21]=[CH:19][O:11][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2ncoc2-c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
4,4'-Dimethylbenzoin (25.0 g), formamide (230 ml) and phosphorus oxychloride (16.0 ml) was mixed and stirred under reflux for 5.5 hours. The reaction mixture was cooled to room temperature and poured into water, and then extracted with diethyl ether twice. The collected organic phases were washed with brine and dried over magnesium sulfate and activated carbon. The mixture was filtered and evaporated in vacuo, and then purified by column chromatography on silica. The solvent was evaporated to afford 4,5-bis(4-methylphenyl)oxazole (15.41 g) as a solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=c1[nH]sc2ccccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Product: CC1CCN(C(=O)Oc2nsc3ccccc23)CC1

Procedure:
In analogy to example 1, 45 mg (0.3 mmol) of benzo[d]isothiazol-3-one were reacted with 58 mg (0.36 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 26 mg (32%), M+H+: 277.14.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH2:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:21]=[N:22][C:23]([C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][C:28]1[N:27]=[C:26]([C:23]2[N:22]=[N:21][C:20]([N:15]3[CH2:14][CH2:13][C:11]4([O:10][CH2:9][C:8](=[O:18])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12]4)[CH2:17][CH2:16]3)=[CH:25][CH:24]=2)[S:30][N:29]=1
Reactant: O=C1COC2(CCNCC2)CN1c1ccccc1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CN(c3ccccc3)C(=O)CO4)nn2)n1

Procedure:
The object product (147 mg, 49%) was obtained in the same manner as in Example 1 and using 4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (230 mg), 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg) and potassium carbonate (140 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:9](O)[CH2:10][OH:11].Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]([C:3]1([CH2:4][C:5]#[N:6])[O:11][CH2:10][CH2:9][O:7]1)([CH3:8])[CH3:1]
Reactant: OCCO
Reactant: CC(C)C(=O)CC#N
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C1(CC#N)OCCO1
Temperature: 40 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
4-Methyl-3-oxopentanenitrile was added to a mixture of ethylene glycol (4.7 mL, 84 mmol) and chlorotrimethylsilane (10.6 mL, 84 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at 40° C. overnight. After cooling to room temperature a solution of 5% sodium bicarbonate (50 mL) was added, the layer were separated and the water phase back extracted three times with diethyl ether. The organics were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to afford 2-(2-isopropyl-1,3-dioxolan-2-yl)acetonitrile (3.38 g, 78%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.21-4.16 (m, 2H), 4.07-3.99 (m, 2H), 2.69 (s, 2H), 2.08-2.01 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C@H:54]2[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:56][C@H:55]2[CH2:68][S:69]([CH3:72])(=[O:71])=[O:70])[C:50]1=[O:73]>CN(C=O)C>[CH3:72][S:69]([CH2:68][C@H:55]1[C@@H:54]([N:51]2[CH2:52][CH2:53][C@H:49]([NH:48][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=3)[C:50]2=[O:73])[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])[CH2:56]1)(=[O:71])=[O:70]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(C)(=O)=O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(C)(=O)=O)C1
Reaction time: 0.17 h
Yield: 129.5 %

Procedure:
3-(Trifluoromethyl)benzoic acid (252.4 mg) was dissolved in DMF (5 mL) and 4-methyl morpholine (0.42 mL) was added prior to the addition of BOP (511 mg). After 10 min, tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (300 mg) was added. The reaction was stirred for 1 h before it was partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-(methylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate (560 mg). MS found: (M+H)+=562.2.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[I:12]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([C:8]([I:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Brc1cn2c(I)cnc2c(Br)n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 8.7 g (31.4 mmol) 6,8-dibromo-imidazo[1,2-a]pyrazine which was prepared according to a procedure described in the Journal of Medicinal Chemistry, 1984, vol. 27, #2, p. 206-212 in 210 mL N,N-dimethylformamide was added 7.42 g N-iodopyrrolidin-2,5-dione in one portion at 23° C. After 18 hours of stirring at 60° C., the solvent was removed in vaccuo and the residue was taken up in dichloromethane and washed with water and saturated sodium thiosulfate solution. The organic phase was dried over sodium sulphate, filtered and the solvent was evaporated to yield 9.46 g (74.8 of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.C1C(=O)N([I:21])C(=O)C1>S(O)(C(F)(F)F)(=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[C:13]([I:21])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2cc(CCO)c(I)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a cooled (0° C.) solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (9.00 g, 50.6 mmol) in 100 mL of TfOH was added NIS (12.5 g, 55.6 mmol), then the mixture was stirred at 0° C. for 2 hrs and then poured into ice-water (500 mL). The solution was extracted three times with 500 mL of EtOAc and the combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Petrol Ether=1:5) to give the desired 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-1(3H)-one (6 g) and isomeric by-product 5-(2-hydroxyethyl)-4-iodo-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(NCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 15 g. of ethyl p-[(p-methoxybenzyl)amino]benzoate, (prepared as described in Example 14) 15 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) are refluxed for 3 hours, acidified while hot with concentrated hydrochloric acid, diluted with water, cooled, filtered and the solid is washed with water to give tan crystals, m.p. 208°-210° C. Recrystallization from ethanol gives off-white crystals, m.p. 209°-210° C.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:29](=[O:30])[CH2:28][N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2CCCCCCC2)=N3)CC1
Yield: 61.6 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.55 mmol) and and 4-methylpiperazin-1-acetic acid (95 mg, 0.60 mmol) according to the procedure described for example 93. Obtained the title compound as a brown solid (140 mg, 62%), MS (ISP) m/e=414.4 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Yield: 10.6 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), 2-bromo-4′-chloroacetophenone (1.6 g), anhydrous potassium carbonate (1.8 g) and ethanol (50 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography. The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.2 g) as colorless crystals.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[NH:21][NH:20][C:19](=[O:22])[CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.O>CC(C)=O>[O:22]=[C:19]1[NH:20][NH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)=[CH:18]1
Reactant: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(c2ccc(-c3cc(=O)[nH][nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 116.6 %

Procedure:
To a suspension of 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-1,2-dihydro-pyrazol-3-one (which was obtained in Example 144) (0.15 g, 0.5 mmol) in acetone (5 mL) was added 5 mL of 10% sulfuric acid. The resulting solution was stirred at room temperature for 4 days. Water (5 mL) was then added, and the acetone was evaporated. The aqueous residue was treated with sodium carbonate until pH 8, and the resulting suspension was filtered. The precipitate was washed with water and ether, and dried in vacuo to give 0.15 g of tan solid; 1H NMR (DMSO-d6) δ 2.41 (t, 4 H), 3.64 (t, 4 H), 5.74 (s, 1 H), 7.04 (d, 2 H), 7.53 (d, 2 H), 9.55 (brs, 1 H), 11.80 (brs, 1 H); MS (ES) m/z: 258 (MH+).