Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N:17]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH3:23]
Reactant: CCOC(=O)C(N)c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(N=Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (170 mL) and benzaldehyde (130 mL) were added to a suspension of ethyl amino-(3,4-dichlorophenyl)-acetate hydrochloride (350 g) in acetonitrile (1.5 L), followed by stirring at room temperature overnight. The insoluble matter was removed through Celite, followed by washing with ethyl acetate. The filtrate was subjected to partitioning with water and then extraction with ethyl acetate. The thus-obtained organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (425 g). The title compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([O:37]C)=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
A solution of (S)-9-bromo-5-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (680 mg, 1.06 mmol) in a mixture of 1N sodium hydroxide (6 mL), THF (6 mL), and methanol (6 mL) was stirred for 3.5 h at room temperature and the solvent was concentrated to ca. 6 mL. To the residue was added 5% potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 608 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][O:12][CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[O:9][CH2:11][O:12][CH3:13]
Reactant: COCCl
Reactant: Oc1ccc(Br)c(O)c1
Solvent: CN(C)C=O
Product: COCOc1cc(O)ccc1Br
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromoresorcinol (1.5 g) in DMF (15 mL) at 0° C. was added Nail (0.19 g). After 20 min., chloromethylmethyl ether (0.636 g) was added in and stirred for 2 hrs. Saturated aq. NAHCO3 was added and the product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography on silica gel with EtOAc in hexanes (1:6).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Br)c2[nH]ccc12
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To 300 ml of a solution of 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene in tetrahydrofuran was added 1 liter of a 1.0M solution of vinyl magnesium bromide (1 mol) in tetrahydrofuran at −60° C. in a nitrogen atmosphere under stirring during 1 hour. To the reaction mixed solution were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the resulting insoluble matters were filtered off. The resulting filtrate was dried over magnesium sulfate, concentrated, and then the resulting residue was purified by a silica gel column chromatography to give 35.5 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1)=[O:4].[CH3:42][NH:43][CH3:44]>O1CCCC1>[CH3:42][N:43]([CH3:44])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CBr)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To the solution of rac-(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 [4-(2-bromo-acetyl)-phenyl]-amide (30 mg, 0.045 mmol) in tetrahydrofuran (1 mL) was added a tetrahydrofuran solution (2 M) of dimethylamine (0.057 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(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 [4-(2-dimethylamino-acetyl)-phenyl]-amide as a yellow solid (10 mg, 35%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:27]3[CH2:28][CH2:29][N:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)[S:8][C:4]=2[CH:3]=1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Yield: 97 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (3 g, 12.1 mmol) in ethanol (50 mL) was added triethylamine (5.04 mL, 36.3 mmol) and 1-cyclopentylpiperazine (1.86 g, 12.1 mmol). The reaction mixture was heated at reflux for 16 h and then concentrated under reduced pressure. The residue was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 4.3 g (99%) of 6-bromo-2-(4-cyclopentylpiperazin-1-yl)benzothiazole.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 850 mg (1.6 mmol) (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester in 6 mL dichloromethane was treated with 2 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 1 hour at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was dissolved in 8 mL diethyl ether, and treated with 3 mL of diethyl ether which had been saturated with hydrogen chloride gas. The solvent was removed under reduced pressure, and the pale yellow oil thus obtained ((S,S)-2-(2-amino-4-methyl-pentylamino)-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide) was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([NH2:25])[CH:24]=1)[CH2:20][OH:21]>>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:16][C:17]2[CH:24]=[C:23]([CH:22]=[C:19]([CH2:20][OH:21])[CH:18]=2)[NH2:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cc(N)cc(CO)c1
Reactant: Clc1c2ccccc2nc2ccccc12
Product: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1

Procedure:
The contacting in step (a) comprises the condensation of 9-chloroacridine and 3,5-diaminobenzyl alcohol to form 3-(9-acridinylamino)-5-hydroxymethylaniline.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:5]2[S:6][C:2]([C:34]3[CH:33]=[N:32][C:31]([S:30][CH3:29])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Br)s2)n(Cc2ccc(F)cc2F)c1=O
Reactant: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)cn1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
6-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (270 mg, 0.57 mmol), 2-methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) pyridine (214 mg, 0.85 mmol), potassium carbonate (236 mg, 1.71 mmol), and tetrakis(triphenylphosphine)palladium (0) (66 mg, 0.057 mmol) were mixed with 6 ml 9:1 DME/H2O (v/v), then heated at 80° C. overnight. All solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (10→40% EtOAC/Hexane, 0.25% Et3N in hexane) to give 1-(2,4-difluoro-benzyl)-6-[5-(6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as an orange solid (276 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 2.61 (s, 3H), 5.45 (s, 2H), 6.66 (s, 1H), 6.82 (m, 1H), 6.88 (m, 1H), 7.09 (m, 1H), 7.12 (d, 1H, J=3.9), 7.27 (m, 2H, mixed with CDCl3), 7.64 (dd, 1H, J=2.4, J=8.4), 8.67 (dd, 1H, J=2.4, J=0.8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 78.8 %

Procedure:
14.2 g of 4'-methoxy-4-nitrochalcone was reacted with 5.4 g of phenylhydrazine in 100 ml of ethanol in the presence of 5 ml of hydrochloric acid by refluxing while heating for 6 hours. After neutralizing the reaction mixture with 50 ml of 1N NaOH, 400 ml of water was added thereto. Decantation-water washing was repeated three times. Crystals formed were recrystallized from 200 ml of acetone to obtain 14.7 g of the desired compound. m.p. 168°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[C:51](B(O)O)[CH:50]=[N:49]2)=[CH:44][CH:43]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:51]4[CH:50]=[N:49][N:48]([C:45]5[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=5)[CH:52]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cnn(-c5ccc(F)cc5)c4)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 75 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) with 1-(4-fluorophenyl)-1H-pyrazol-4-ylboronic acid (CAS [1072945-89-1]) and tetrakis(triphenylphosphine)-palladium(0) as the catalyst yielded the title compound (75% yield) as a white foam. MS (ISP): m/z=689.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[CH:40]12[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]1)[CH2:43][NH:42][CH2:41]2.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:42]2[CH2:41][CH:40]3[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (226 mg, 0.39 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.56 mmol), NaHCO3 (196 mg, 2.33 mmol) in NMP (4 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.38 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed m/z 758.3 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C[C@@H]1COC(=O)N1
Product: COC(=O)c1ccc(CN2C(=O)OC[C@H]2C)cc1
Yield: 74.4 %

Procedure:
Using methyl 4-bromomethylbenzoate (1.00 g) and (R)-4-methyloxazolidin-2-one (0.49 g) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (0.81 g) was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:32](=[O:34])[CH3:33])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Yield: 72 %

Procedure:
To a stirred solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (250 mg, 0.753 mmol) and triethylamine (200 μl. 1.88 mmol) in dichloromethane (2 ml) was added dropwise acetic anhydride (78 μl, 0.828 mmol). Reaction left at ambient temperature until reaction complete. Dichloromethane (10 ml) added to the reaction, the organic phase extracted with saturated NaHCO3 (3×10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as an oil (203 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.94 (d, 2H), 4.95-5.02 (broad, 1H), 4.24-4.38 (m, 1H), 3.79-3.88 (m, 2H), 3.52-3.64 (m, 2H), 3.45 (d, 2H), 2.70-2.88 (m, 3H), 2.36-2.45 (m, 2H), 1.98-2.10 (m, 4H), 1.78-1.90 (m, 7H), 1.05 (d, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)[C:8](O)=[O:9])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)=[O:30])[C:8]([N:46]1[CH2:47][CH2:48][N:43]([CH:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]2)[CH2:44][CH2:45]1)=[O:9])[CH3:2]
Reactant: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1CCC(N2CCNCC2)CC1
Product: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-diethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH2:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[CH3:19]>>[CH2:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:1](=[O:3])[CH3:2])=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[CH3:19]
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN1C(=O)Cc2cc(C(C)=O)ccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a mixture of 29.25 g. (0.373 mole) of acetyl chloride and 65.9 g. of aluminum chloride in 60 ml. of nitrobenzene was added gradually 20.0 (0.124 mole) of 1-ethyloxindole. The reaction warmed to about 45° C. with an evolution of gas. After stirring for one hour the reaction was heated to 100° C. for one hour and allowed to stir at room temperature over night. The reaction mixture was poured into 2 l. of ice with stirring. After 30 minutes the product was filtered, air dried and dissolved in 200 ml. of methylene chloride. The solution was dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from toluene, 14.44 g. (57.3% yield), m.p. 141°-145° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18]>CS(C)=O>[CH2:16]([O:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: Cc1cnc(CCCC#N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1cc(C)cnc1CCCC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine from Example 3(a) (1.5 g), in dimethyl sulphoxide (11 ml) was first treated with sodium hydride (0.2 g) and then with n-propyl iodide in dimethyl sulphoxide (3 ml) at 17°-20° C. After stirring for four hours at room temperature, the solvent was removed in vacuo and the residue partitioned between chloroform and water, the chloroform extract was evaporated to dryness to give 3-n-propyloxy-2-(3-cyanopropyl)-5-methylpyridine (1.79 g) N.M.R. (CDCl3), assignment, δ(p.p.m.), multiplicity; O(CH2)2CH3, 1.07; t; OCH2CH2CH3, 1.86; m; CH2CH2CN, 2.12, m; CH2CN, 2.40, m; 5-CH3, 2.30, s; CH2 (CH2)2CN, 3.94, m; OCH2, 3.91, t; 4-H pyridyl, 6.96, m; 6-H pyridyl, 7.91, m;
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.CCCCCC>CCOCC>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCN
Solvent: CCCCCC
Solvent: CCOCC
Product: CNCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
N-Methyl ethylenediamine (15 g, 202.3 mmol) was added dropwise to a stirred solution of ethyl trifluoroacetate (28.7 g, 204.34 mmol) in dry Et2O (50 mL) at 0° C. The resulting solution was stirred at room temperature for 2 hours. Hexane (75 mL) was added and the solution was left at −20° C. for 16 hours to produce a white precipitate which was removed by filtration, washed with Et2O (100 mL) and dried in vacuo for 3 hours to afford the title compound (29.4 g, 85%). 1H NMR (300 MHz, CDCl3) δ 3.42 (t, J=5.8 Hz, 2H), 2.80 (t, J=5.9 Hz, 2H), 2.43 (s, 3H); mass spectrum (API-TIS) 171 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5].C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([O:22][C:23]([NH:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC[C@H](N)C1NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)OCc1ccccc1)C1NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution obtained by dissolving 3(S)-amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 ml) and water (40 ml), sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 ml, 39.01 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours.