Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:34]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCN(C(=O)C2CC2)CC1
Temperature: 18 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (I)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. 0-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[C:7]([Cl:28])[CH:6]=1)(=[O:3])[CH3:2].[CH3:29]I>>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)=[O:10])=[C:7]([Cl:28])[CH:6]=1)[CH3:29])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
0.8 g of 1-[4-(N-methylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine (see Example 8) is methylated in a manner analogous to that described in Example 5 with 0.3 g of methyl iodide to form 1-[4-(N-acetyl-N-methylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine. It has a melting point of 162°-163°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[NH:33][CH:32]=[N:31][N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[N:33]=[CH:32][N:31]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A mixture of 5-(benzyloxy)-2-methyl-3-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (440 mg, 0.94 mmol) produced in Example 30-B(x), 3,4-dihydro-2H-pyran (0.17 mL, 1.9 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 day. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give 5-(benzyloxy)-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridine (430 mg, 84%) as a colorless solid.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])[C:31]2=[O:47])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:6][N:7]([CH3:9])[CH3:8])[CH:32]([NH:38][P:39]([O:41][CH2:42][CH3:43])([O:44][CH2:45][CH3:46])=[O:40])[C:31]2=[O:47])=[O:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)OCC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)CSC12)OCC
Reaction time: 0.2 h

Procedure:
t-Butoxy-bis-dimethylaminomethane (6 cc) is added to a solution of 2-benzhydryloxycarbonyl-7-diethoxyphosphorylamino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in dry N,N-dimethylformamide (100 cc) at 80° C. After 12 minutes at 80° C., the reaction mixture is poured into ethyl acetate (400 cc) and washed with distilled water (5×250 cc). After drying over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-diethoxyphosphorylamino-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (10.5 g) is obtained in the form of an orange crystalline solid. This product is purified by crystallisation from ethyl acetate (30 cc), and 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-diethoxyphosphorylamino-8-oxo-5 -thia-1-azabicyclo [4.2.0]oct-2-ene (E isomer) (5.3 g) is obtained in the form of a yellow crystalline powder (m.p.=193°-194° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(OCC)C>[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CN1CCc2cc(O)ccc21
Reactant: CC(C)c1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3C)cc1
Reaction time: 0.03 h
Yield: 14.5 %

Procedure:
To a solution of 1-methylindolin-5-ol (18 mg, 0.12 mmol) in 0.6 mL of dry diethyl ether was added sodium hydride (55%, 19 mg, 0.43 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, 4-isopropylphenylisocyanate (29 μL, 0.18 mmol) was added with additional stirring for 5 min to 10 min. After the reaction mixture was quenched with water (1 mL), the solution was extracted with diethyl ether (10 mL). The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40) to obtain the title compound (5.4 mg, 14%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2)CC1
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: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)CC1

Procedure:
202 mg (0.68 mmol) of 4-(2-chloropyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, 256 mg (0.81 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane and 187 mg (1.36 mmol) of potassium carbonate are dissolved in 6 ml of acetonitrile and 650 μl of water. The reaction mixture is degassed a number of times, 78 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, the mixture is irradiated in the microwave at 120° C. for 90 min, subsequently diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by column chromatography on RP silica gel.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3](=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]#[CH:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3](=[N:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]=[CH:5][S:26][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: C#CC(=Nc1ccccc1)N(C)c1ccccc1
Reactant: Sc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CN(C(C=CSc1ccc(Cl)cc1)=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
N-methyl-N-phenyl-N′-phenylpropynamidine (0.23 g) was dissolved to chloroform (5 ml), chloroform (5 ml) solution of 4-chlorothiophenol (0.14 g) was added dropwise under ice-cooling and stirred for 14 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to obtain N-methyl-N-phenyl-N′-phenyl-3-(4-chlorophenylthio)acrylamidine (0.22 g) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:21])=[CH:13][CH:12]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: Fc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
To a stirred solution of 2-chloro-4-fluoropyridine (1.261 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (2) (750 mg, 3.83 mmol) in NMP (40 mL), at −20° C., was added potassium tert-butoxide (1.290 g, 11.50 mmol). The reaction mixture was allowed to warm to RT. After 2.5 hr, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL then 2×80 mL). The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release eluting with 1% NH3 in MeOH solution and the solvent was removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine (3) (1.019 g, 92%) as a brown solid: m/z 271 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]1COCC1.[C:6]([N:16]=[C:17]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O>CO>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[N:16][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: C1CCOC1
Reactant: O=C(O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Product: COC(=O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 19 h
Yield: 42 %

Procedure:
To a THF (300 mL) solution of compound 31 (50.8 g, 0.12 mol) was added carbonyldiimidazole (21.4 g, 0.132 mol). The resultant suspension was stirred for 1 h at room temperature. Methanol (75 mL) was added, followed by an additional stirring of the solution for 19 h. The solution was concentrated, and the residue was partitioned between water and ether. The organic phase was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/1:1) to afford 22.8 g (42%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.70 g, 1.80 mmol) in dimethylformamide (14 ml) was added ceasium carbonate (2 g) followed by methyl bromoacetate (255 μl, 2.70 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate, and the combined organic phases dried over magnesium sulfate and concentrated in vacuo to provide a yellow solid. No further purification was required. Yield: 0.51 g, 61%; LCMS method: basic, RT: 3.77 min, MI: 462 [M+1].
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[C:14](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CS(=O)c1cccc(CC(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A solution of [3-(methylsulfinyl)phenyl]acetic acid (1.31 g, 6.60 mmol) and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirred at room temperature for 15 minutes, then methanol (2.1 mL, 52.8 mmol) was added. After 10 minutes the reaction was briefly warmed to near reflux temperature, then allowed to cool to room temperature. After 20 minutes, the reaction was partitioned between EtOAc and NaHCO3/brine mixture. The EtOAc layer was washed with dilute brine, dilute HCl solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a yellow-orange oil (1.14 g, 82%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][NH:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12CNCC1CCN2[C:24]([O:26][CH2:27][CH3:28])=[O:25].ClC(OCC)=O>>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][N:13]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC2CNCC21
Reactant: c1ccc(CN2CC3CCNC3C2)cc1
Agent: CCOC(=O)Cl
Product: CCOC(=O)N1CCC2CN(Cc3ccccc3)CC21

Procedure:
Ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate 7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example Oa) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane-2-carboxylate, and this is then debenzylated hydrogenolyrically analogously to Example Jd). A colorless oil of boiling point 90° C./0.1 mbar is obtained.
Reaction SMILES: [CH2:1](I)[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:14]2[N:15]=[C:16]([CH3:25])[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:18](=[O:19])[C:13]2=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:1][CH3:2])=[CH:31][CH:32]=2)=[C:14]2[N:15]=[C:16]([CH3:25])[N:17]([CH2:20][C:21]([F:24])([F:22])[F:23])[C:18](=[O:19])[C:13]2=[N:12]1
Reactant: Cc1nc2c(-c3ccc(O)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (88 μL, 1.1 mmol) was added to a mixture of 2-(2-chlorophenyl)-3-(4-hydroxyphenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (6A-1, 50 mg, 0.11 mmol), Cs2CO3 (55 mg, 0.17 mmol) in NMP (2 ml) at 85° C. The reaction mixture was stirred at this temperature for 5 h, cooled to room temperature, and diluted with 0.5 M citric acid. The aqueous solution was extracted with EtOAc (2×), and the combined organic extracts were washed with 1 M K2CO3, saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified on a Chromatotron using 1 mm plates and 33% EtOAc/hexanes to give the desired product 7A-1 as an amorphous glass: MS (m/z) 435.4 (M+H)+; 1H NMR (400 MHz, CD2Cl2): δ 7.61–7.46 (m, 4H), 7.25–7.20 (m, 2H), 6.74–6.69 (m, 2H), 5.02 (q, J=7.1 Hz, 2H), 2.65 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1)=[O:11].Br[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)=[O:11])=[N:31][CH:32]=1
Reactant: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 503 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(F)c(F)cc3F)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 38.9 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-6, 0.200 g, 0.493 mmol) and 2,4,5-trifloro aniline (0.108 g, 0.740 mmol), trimethyl aluminium (2M solution in toluene) (0.071 g, 0.986 mmol) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.11 (s, 2H), 7.21 (m, 2H), 7.53 (m, 2H), 7.73 (q, J=7.8 Hz, 1H), 8.48 (m, 1H), 10.11 (bs, 1H), 11.00 (s, 2H); MS [M+H]+: 521.14.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(O)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanol (113.4 mg, 0.25 mmol) in DCM (10 mL) was added PDC (236 mg, 0.63 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was then filtered through a pad of silica gel, and the pad was washed by 5% EtOAc in DCM (200 mL). The filtrate was concentrated in vacuo to afford (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone as a colorless oil. MS (ES+): 450.0 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:28]1[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2cccc(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 91 mg (0.55 mmol) of 3-hydroxy-benzotrifluoride and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue purified by column chromatography (20 g silica gel, diethyl ether/heptane 1:1) to yield 182 mg (74%) product as a white solid. MS (ISP) 495.5 (M+H)+.