Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:19](=[C:16]1[CH:17]=[CH:18][NH:13][CH:14]=[CH:15]1)[C:5]2=[O:12]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: Cc1ccncc1
Product: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under N2 atmosphere, a mixture of 30 g (132 mmol) 5-bromoisobenzofuran-1,3-dione (|4-bromophthalic acid anhydride; Apin, GB) and 12.87 ml (132 mmol) 4-picoline is heated for 15 h to 180° C. The resulting black mass is cooled to 100° C., mixed with 160 ml ethanol,boiled for 2 hours, and filtered off. The dried residue is triturated in a mortar, boiled further for 1 h in 180 ml ethanol, filtered, and washed with ethanol. The residue is dissolved at 140° C. in 90 ml DMEU, cooled, mixed with 250 ml ethyl acetate and filtered (→residue is washed out with ethyl acetate and discarded). The ethyl acetate from the filtrate is evaporated off and the residue then diluted with 260 ml acetonitrile, the title compound crystallizing out in the process: HPLC: tRet(Grad20-100)=10.4; MS (M)+=301/303.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL, 1.40 mmol, 2M in tetrahydrofuran) at −78° C. over 5 minutes. After 30 minutes, 1,2-dibromo-1,1,2,2,-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 4 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to afford a dark solid residue. The residue is purified by flash column chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 190–191° C.; 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.C(O)=[O:16]>[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: O=CO
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Agent: Cl[Fe](Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 93 %

Procedure:
268 g of 2,3,4,5-tetrafluorobenzotrichloride were added to the distillation residue (approximately 20 g) and 2.7 g of iron(III) chloride were added. The mixture was reacted with formic acid in a similar manner to a). 198 g (93% of theory) of 2,3,4,5-tetrafluorobenzoyl chloride were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:14]([F:17])([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:22][C:21]1[CH:20]=[CH:19][C:18]([C:13]([F:12])([F:25])[C:14]([F:15])([F:16])[F:17])=[CH:24][CH:23]=1)=[O:9]
Reactant: Nc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-pentafluoroethyl-aniline to afford a white crystalline solid. HPLC (Condition 4) tR=6.61 min, UPLC-MS (Condition 3) tR=1.32 min, m/z=429 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1.O.[NH2:18][NH2:19]>CO.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:18][NH2:19])=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1
Reactant: CC1(C)COB(c2ccc(C(=O)O)cc2)O1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Product: CC1(C)COB(c2ccc(C(=O)NN)cc2)O1
Yield: 72 %

Procedure:
58.5 g (250 mmol) of 4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoic acid are dissolved in 250 ml of methanol, and 12.5 g (250 mmol) of hydrazine hydrate and 1.5 g (12.5 mmol) of 4-dimethylaminopyridine are added. The solution is refluxed for 12 hours. Removal of 200 ml of methanol by distillation gives 44.6 g (180 mmol, 72%) of product.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.O>ClCCl>[CH:14]12[O:6][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Reaction time: 18 h
Yield: 78.7 %

Procedure:
3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS2O5 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL×2). The organics were combined and washed with 5% aqueous K2CO3 solution (100 mL×3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to a stirred solution of 5% NaS2O5(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed <0.5 mg/mL peroxide. The layers were separated and aqueous layer washed with further DCM (2×50 mL). The combined organics were then dried (Na2SO4). and concentrated in vacuo to afford the crude product as a pale-gold oil. The crude product was purified by silica gel chromatography, (340 g Si), eluting with 30→80% EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil—benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (12.75 g, 54.7 mmol, 79% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][N:15]4[C:14](=[O:21])[CH2:13][CH2:12]3)[CH:18]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:40])[C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:27]=[N:28][CH:29]=1>>[O:21]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]13)[CH:18]=[C:9]([C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32]([C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:40])[CH:27]=[N:28][CH:29]=1)[CH:10]=2
Reactant: CC1(C)OB(c2cc3c4c(c2)CCN4C(=O)CC3)OC1(C)C
Reactant: O=C(NCc1cncc(Br)c1)c1ncccc1Cl
Product: O=C(NCc1cncc(-c2cc3c4c(c2)CCN4C(=O)CC3)c1)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 45, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one has been coupled to N-((5-bromopyridin-3-yl)methyl)-3-chloropicolinamide (intermediate A-56) to give the title compound as off-white solid. MS: 419.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:14]([N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCNCc1ccccc1
Reactant: CSCC[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSCC[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)N(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-L-methionine and ethyl 4-benzylaminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-L-methionyl]-4-benzylaminobutyric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])[NH2:28]>>[CH3:23][O:22][C:8]1[CH:7]=[C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([F:32])=[C:25]([Cl:24])[CH:26]=3)[C:11]2=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1

Procedure:
condensing, 4-chloro-7-methoxy-6-(3-morpholino propoxy) quinazoline of the formula VII with 3-chloro-4-fluoroaniline to obtain gefitinib of formula I.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[CH:19]([CH3:25])[C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([C:20](=[O:21])[CH:19]([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]2[CH3:1])[CH3:25])[CH2:24][CH2:23]1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(=O)C1CC1
Yield: 54 %

Procedure:
The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300.00 mg, 1.29 mmol), 2-bromo-1-cyclopropylpropan-1-one (342.98 mg, 1.94 mmol), Cs2CO3 (841.63 mg, 2.58 mmol), KI (42.88 mg, 0.26 mmol) in DMF (4 ml) were stirred at 25° C. for 18 h. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column (Eluent: PE:EtOAc=10:1) to get tert-butyl 1-(1-cyclopropyl-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (230 mg, yield 54%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7](F)=[C:6]([F:13])[C:5]=1[F:14])[CH:2]=[CH2:3].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([NH:16][NH2:17])=[C:6]([F:13])[C:5]=1[F:14])[CH:2]=[CH2:3]
Reactant: C=CCc1c(F)c(F)c(F)c(F)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: C=CCc1c(F)c(F)c(NN)c(F)c1F

Procedure:
Allylpentafluorobenzene [41.6 g; described by Harper et al, J. Org. Chem., 29, 2385 (1964)] was added to a solution of hydrazine hydrate (100 ml) in ethanol (150 ml) and the mixture was heated at reflux for 24 hours. The solid precipitate which formed was collected by filtration and washed with ethanol and hexane to give 4-allyl-2,3,5,6-tetrafluorophenylhydrazine (18.8 g), m.p. 82°-84° C., in the form of colourless crystals. The filtrate was evaporated to dryness and the yellow solid thus obtained was washed with ethanol and hexane to give a further quantity (22.0 g) of 4-allyl-2,3,5,6-tetrafluorophenylhydrazine, m.p. 79°-81° C., in the form of a cream-coloured solid.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[NH:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6](=[O:12])[CH2:5]1)[CH3:3].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[Si:22]([O:1][C@H:2]([C@H:4]1[NH:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6](=[O:12])[CH2:5]1)[CH3:3])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: C[C@H](O)[C@@H]1CC(=O)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(C)(C)N1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-one (0.11 g, 0.64 mmol) in DMF (3 mL) were added imidazole (0.13 g, 1.93 mmol) and TBSCl (0.14 g, 0.96 mmol). The mixture was stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 65 mg (35%) of (S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.99 (dq, J=6.3, 2.8 Hz, 1H), 2.96-3.04 (m, 1H), 2.21-2.32 (m, 3H), 2.13 (d, J=13.1 Hz, 1H), 1.26 (s, 3H), 1.12 (d, J=6.1 Hz, 3H), 1.05 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11]/[CH:12]=[CH:13]/[C:14]([O:16][Si](C)(C)C)=[CH2:15].[C:21]1([CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[CH:27]([CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[CH:12][O:11]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1C=COC(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of boron trifluoride diethyl etherate (7.8 g, 55 mmol) in dry ether (50 ml) was added to a stirred mixture of E-1-methoxy-3-trimethylsilyloxybuta-1,3-diene (8.3 g, 48 mmol), diphenylacetaldehyde 1 (11.4 g, 58 mmol) and dry ether (300 ml) cooled to −78° C. After one hour, the mixture was allowed to reach 0° C. for three hours. The deep red reaction mixture was quenched with saturated aqueous NaHCO3, and the mixture was allowed to come to room temperature. The organic phase was separated and the aqueous phase was extracted with ether (3×70 ml). The combined organic phases were washed with brine, and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure and purification of the crude product by chromatography (hexane/ethyl acetate 8:2) gave 2-diphenylmethyl-2,3-dihydro-4H-pyran-4-one 2 (10.2 g, 80.2%, yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc(F)ccc1F
Reactant: BrCCCBr
Product: Fc1ccc(F)c(OCCCBr)c1

Procedure:
Analogously to Example 91b, 1.40 g of 2,5-difluorophenol and 21.5 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.59 (1:3 EtOAc-heptane); Rt=4.84.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26]1([CH2:32][C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:26]1([CH2:32][C:33]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[O:12])=[CH:24][CH:25]=3)[CH2:6][CH2:5]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCN(C(=O)Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-piperazin-1-yl-N-quinolin-3-yl-benzamide (75 mg, 0.284 mmol), phenylacetic acid (51 mg, 0.375 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU)(118 mg, 0.30 mmol) and N,N—N,N-diisopropylethylamine (0.110 mL, 0.626 mmol) in acetonitrile (2 mL) was heated to 80° C. The solution was cooled to room temperature and the product crystallized. The product was collected by filtration washed with acetonitrile to give 63 mg (49%). MS: m/z 451 (MH+). 1H NMR (DMSO-d6): δ 3.24-3.34 (m, 4 H), 3.63-3.69 (m, 4 H), 3.79 (s, 2 H), 7.05 (d, 2 H), 7.22-7.46 (m, 5 H), 7.54-7.67 (m, 2 H), 7.92-7.99 (m, 4 H), 8.82 (d, 1 H), 9.15 (d, 1 H) and 10.40 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36]([C:35]3[CH:34]=[N:33][C:32]([N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)=[O:37])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)nc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-morpholinonicotinic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 571.1 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][F:26])[C@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CO.[Pd]>[F:26][CH2:25][CH2:24][N:8]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCF)[C@H]1CCNC1
Reaction time: 2 h

Procedure:
To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(2-fluoroethyl)amino)pyrrolidine-1-carboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate. To a solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate (0.92 g, 3.95 mmol) and K2CO3 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50° C. for 18 hours. After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes) to afford tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate (0.58 g, 48%).
Reaction SMILES: Cl.[N:2]12CCC([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[CH3:11][O:12][C:13]([O:16][CH3:17])([CH3:15])[CH3:14].CS(O)(=O)=O>P([O-])([O-])([O-])=O>[CH3:11][O:12][C:13]1([O:16][CH3:17])[CH:15]2[CH2:6][CH2:7][N:2]([CH2:3][CH2:4]2)[CH2:14]1
Reactant: COC(C)(C)OC
Reactant: O=C1CN2CCC1CC2
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC1(OC)CN2CCC1CC2

Procedure:
A mixture of 3-quinuclidinone hydrochloride (5.00 g, 30.9 mmol), 2,2 dimethoxypropane (50 ml), and methanesulfonic acid (0.1 ml) was refluxed for 8 h. The reaction mixture was poured in pH 7.4 phosphate buffer (20 ml) and washed 4 times with ethyl acetate. The aqueous phase was made basic by the addition of 4 M NaOH. Extraction with 3 portions of ethyl acetate gave, after drying and evaporation the title compound as a colorless oil. Yield 4.00 g (75%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]([CH3:18])([N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]1)[CH3:9])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][CH:25]([NH:31][CH:32]([CH2:36][CH2:37][CH3:38])[C:33](O)=[O:34])[CH2:24][CH2:23]2>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]([N:10]1[CH:14]=[C:13]([NH:15][C:33](=[O:34])[C@@H:32]([NH:31][CH:25]2[CH2:24][CH2:23][C:22]3[C:27](=[C:28]([F:30])[CH:29]=[C:20]([F:19])[CH:21]=3)[CH2:26]2)[CH2:36][CH2:37][CH3:38])[N:12]=[CH:11]1)([CH3:18])[CH3:9])[CH3:2]
Reactant: CCOCCNCC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCCOCC)cn1

Procedure:
(2-Ethoxy-ethyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 492.6 m/z (M+1).
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Oc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a solution of 134 (0.28 g, 1.12 mmol) in ethanol (20 mL) was added sodium borohydride (0.042 g, 1.12 mmol). After stirring at room temperature for 15 min, the reaction was quenched with water and extracted with ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (25%/75%) to give 135 (0.28 g, 95% yield): 1H-NMR (400 MHz, chloroform-d) δ 8.29 (d, J=8.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.61 (m, 1H), 7.53 (m, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 7.05 (dd, J=8.6, 1.2 Hz, 2H), 6.88 (d, J=7.8 Hz, 1H), 5.12 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:27]([C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[CH2:37][C:38]([F:41])([F:40])[F:39])[CH:28]([CH3:30])[CH3:29]>>[NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:35]3[CH2:34][CH2:33][N:32]([CH2:37][C:38]([F:40])([F:41])[F:39])[C@@H:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:36]3)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)C[C@H]1CNCCN1CC(F)(F)F
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1
Product: COC[C@H](C)Nc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(N2CCN(CC(F)(F)F)[C@@H](CC(C)C)C2)n1

Procedure:
The reaction of (S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (74 mg, 0.2 mmol, Example 122(b)) with (S)-2-isobutyl-1-(2,2,2-trifluoroethyl)piperazine (89 mg, 0.4 mmol) under the conditions of Example 34 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 565 (M+1).