Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[CH2:18]([C:20]1[NH:24][C:23]([C:25](O)=[O:26])=[N:22][C:21]=1[C:28]([F:31])([F:30])[F:29])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:18]([C:20]1[NH:24][C:23]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:26])=[N:22][C:21]=1[C:28]([F:30])([F:31])[F:29])[CH3:19]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (178 mg, 0.73 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (100 mg, 0.48 mmol), WSC hydrochloride (280 mg, 1.46 mmol) and HOBT (66 mg, 0.49 mmol), to obtain 173.5 mg of the title compound as a white foamy substance (91%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:8].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:7]([C:6]2[C:5]([O:23][CH3:24])=[CH:4][C:3]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:2]([Cl:1])[CH:22]=2)=[O:8])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(I)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccccc2)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-4-iodo-2-methoxybenzoyl)piperazine-1-carboxylate (300 mg, 0.56 mmol), phenylboronic acid (82 mg, 0.67 mmol), Pd(PPh3)4 (129 mg, 0.1 mmol), Na2CO3 (180 mg, 1.68 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (219 mg, 80% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([C:27]#[C:28][CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:28]#[C:27][CH:24]3[CH2:26][CH2:25]3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NCC#CC2CC2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC#CC2CC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.5 g) in 2-propanol (20 mL) were added 4-[(3-cyclopropylprop-2-yn-1-yl)amino]-1,3-thiazol-2(5H)-one (1.29 g) and piperidinium acetate (0.64 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.56 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:23]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>C1(C)C=CC=CC=1.C(O)C.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.O>[CH2:26]([O:25][C:23]([C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[CH:31]=[CH:30][CH:29]=1)=[O:24])[CH3:27]
Reactant: Clc1cnc(OCc2ccccc2)c(-c2ccccc2Br)c1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
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: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)cnc2OCc2ccccc2)c1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
3-(2-Bromophenyl)-5-chloro-2-(benzyloxy)pyridine (80 mg, 0.214 mmol) and 3-(carbethoxy)phenylboronic acid (42 mg, 0.214 mmol) were dissolved in toluene/ethanol (1:1 1 ml) under nitrogen. Potassium carbonate (236 mg, 1.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.0214 mmol) were added and the resulting mixture was heated at 70° C. in a Smithoreator® microwave for 15 minutes. After cooling, diethyl ether (5 ml) and water (5 ml) were added. The organic layer was washed with water, dried (MgSO4) and evaporated. The product was purified by flash chromatography (silica gel, 2-3% ethyl acetate:isohexane) to give the title compound as a clear oil (31 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19](=[O:20])[O:18]2)=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 6.2 g of 2-(4-isobutylphenyl)propionic acid in 30 ml of chloroform and 3.4 g of triethylamine, a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform is added. The solution thus obtained is stirred 24 hours at room temperature (about +22° C.), the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 8.1 g of phthalidyl 2-(4-isobutylphenyl)propionate; m.p. 62°-65° C. IR: 1795 and 1780 cm1
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: Cc1c(F)ccc(C=O)c1F
Reactant: O=C(O)CC(=O)O
Product: Cc1c(F)ccc(C=CC(=O)O)c1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h30) between 2,4-difluoro-3-methyl-benzaldehyde (1.560 g; 9.744 mmol) and malonic acid (1.926 g; 18.515 mmol) gave the product 3-(2,4-difluoro-3-methyl-phenyl)-acrylic acid as a pale yellow solid (1.600 g; 83%). LC-MS: tR=0.86 min; [M+H]+: no ionisation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].O1CCCC1.Cl>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15]([N:29]([CH3:30])[CH3:28])(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COc1cc(-c2noc(C)n2)c(S(=O)(=O)Cl)cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(S(=O)(=O)N(C)C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonylchloride, dimethyl-amine hydrochloride (203 mg) and tetrahydrofuran (20 mL) was added triethylamine (0.693 mL) under ice-bath cooling. After stirring at room temperature overnight, 2 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonamide.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][C:16]([CH3:34])([CH3:33])[C:17]([NH:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=1)=O>C1(C)C=CC=CC=1>[CH3:15][C:16]([C:17]1[O:32][C:21]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=2)=[N:20][N:19]=1)([CH3:34])[CH3:33]
Reactant: Cc1cc(C(=O)NNC(=O)C(C)(C)C)ccc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nnc(C(C)(C)C)o2)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
Phosphorus pentoxide (10 g) is added to a suspension of N′-(2,2-dimethylpropanoyl)-3-methyl-4-nitrobenzhydrazide (5.1 g) in toluene (200 ml). After refluxing for 2 h, the reaction mixture is poured into ice-water and extracted with diethyl ether. The organic phases are combined, dried over magnesium sulphate, evaporated and purified by chromatography on silica (eluent: 2/1 diethyl ether/petroleum ether) to give 2-(1,1-dimethylethyl)-5-(3-methyl-4-nitrophenyl)-1,3,4-oxadiazole.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]3[CH:7]=1)=O.[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:27][NH:28]2)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH:31]3[CH:4]([C:6]4[C:16]5=[C:17]6[C:12](=[CH:13][CH:14]=[CH:15]5)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]6[CH:7]=4)[C:3](=[O:2])[NH:34][C:32]3=[O:33])=[CH:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO)C2
Reactant: NC(=O)Cc1c[nH]c2cc(Br)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(Br)ccc12

Procedure:
Beginning with (5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxoacetic acid methyl ester and (6-bromo-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(OC([N:8]([C:12]1[S:13][CH2:14][C@@H:15]2[C@@H:20]([CH3:21])[O:19][CH2:18][C@:16]2([C:22]2[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:23]=2[F:29])[N:17]=1)C([O-])=O)=O)(C)(C)C.O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(O)=O.[Na+].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH3:21][C@@H:20]1[C@@H:15]2[C@@:16]([C:22]3[CH:27]=[C:26]([C:36]4[CH:37]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=4[F:38])[CH:25]=[CH:24][C:23]=3[F:29])([N:17]=[C:12]([NH2:8])[S:13][CH2:14]2)[CH2:18][O:19]1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: C[C@H]1OC[C@]2(c3cc(Br)ccc3F)N=C(N(C(=O)[O-])C(=O)OC(C)(C)C)SC[C@H]12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[C@H]1OC[C@]2(c3cc(-c4cc(F)ccc4F)ccc3F)N=C(N)SC[C@H]12
Temperature: 100 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
tert-Butyl[(4aS,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]imidodicarbonate (0.15 g, 0.34 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL). The resulting solution was heated to 100° C. and to it was added (2,5-difluorophenyl)boronic acid (0.11 g, 0.67 mmol), cesium carbonate (0.659 g, 2.02 mmol) and dichloropalladium-triphenylphosphane (0.047 g, 0.067 mmol) and the reaction was stirred at 100° C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL). After 1 hour, the solvents were removed in vacuo. The residue was neutralised with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified using column chromatography (gradient 0-15% MeOH in EtOAc) to give the title compound (18 mg, colourless solid). 1H NMR (400 MHz, CDCl3) δ ppm: 7.50-7.58 (m, 2 H), 7.09-7.2 (m, 3 H), 6.97-7.06 (m, 1 H), 4.61 (d, J=10.1 Hz, 1 H), 4.35-4.47 (m, 1 H), 4.21 (dd, J=10.0, 1.6 Hz, 1 H), 3.28 (dd, J=13.5, 3.7 Hz, 1 H), 3.03 (dt, J=8.1, 4.0 Hz, 1 H), 2.91 (dd, J=13.6, 4.0 Hz, 1 H), 1.44 (d, J=6.1 Hz, 3 H)
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19]C)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:2][NH2:3])=[O:19])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN

Procedure:
0.4 g of hydrazine hydrate is added to a solution of 1.3 g of methyl 3-(tert-butoxycarbonylamino)thiophene-2-carboxylate in 10 ml of ethanol and the mixture is heated to reflux for 5 hours. After the volatile fractions had been removed under reduced pressure at 40° C., the remaining oil was purified by column chromatography (silica gel, eluent: methylene chloride:methanol=95:5).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12]3=[O:19])[S:10][C:6]=2[CH:5]=1.[BH4-].[Na+].C(O)(=O)C>CO>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([N:11]3[C:12](=[O:19])[C:13]([CH3:18])=[C:14]([CH3:17])[CH:15]3[OH:16])[S:10][C:6]=2[CH:5]=1
Reactant: CC1=C(C)C(=O)N(c2nc3ccc(OC(F)(F)F)cc3s2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(C)C(O)N(c2nc3ccc(OC(F)(F)F)cc3s2)C1=O
Reaction time: 3 h
Yield: 88.7 %

Procedure:
N-(6-trifluoromethoxy-2-benzothiazolyl)-dimethylmaleimide (3.42 g) was added to methanol (150 ml), and sodium borohydride (0.19 g) was added at room temperature over 15 minutes. The mixture was further stirred for 3 hours. After the reaction, the reaction mixture was neutralized with acetic acid, and methanol was evaporated under reduced pressure. The residue was mixed with water and extracted with chloroform. Chloroform extracts were combined, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The solid residue was washed with a small amount of diethyl ether to give the desired N-(6-trifluoromethoxy-2-benzothiazolyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (3.05 g). m.p. 228°-231° C. ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1Br
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 2-bromo-4-fluoro-1-nitrobenzene (30 g, 137.61 mmol, 1.00 equiv) in N,N-dimethylformamide (450 mL), piperidine (13.974 g, 162.68 mmol, 1.20 equiv), and potassium carbonate (56.718 g, 411.00 mmol, 2.99 equiv). The resulting solution was stirred overnight at 75° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 300 mL of dichloromethane. The resulting mixture was washed with 2×100 mL of water and 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50). This resulted in 19 g (49%) of 1-(3-bromo-4-nitrophenyl)piperidine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:28]2[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]2)=[CH:3][CH:4]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](O)C3)cc2)C1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A suspension of (S)-2-(4-bromophenyl)-1,4-di(t-butoxycarbonyl) piperazine (1.33 g, 3.00 mmol), (R)-3-pyrrolidinol (520 mg, 4.20 mmol), palladium acetate (27 mg, 0.12 mmol), 2-(di-t-butylphosphino)biphenyl (72 mg, 0.24 mmol), and sodium t-butoxide (808 mg, 8.41 mmol) in tert-butanol (20 mL) was heated at 90° C. for 3.5 h. After dilution with ethyl acetate, the resulting mixture was passed through a Celite column. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting 10-50% ethyl acetate-hexane to afford (S)-1,4-di-(t-butoxycarbonyl)-2-(4-((R)-3-hydroxypyrrolidino) phenyl)piperazine (733 mg, 54.5%) as a yellow foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.O.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH3:34][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@H]3CCCCN3)ccnc21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCCC[C@@H]1COc1ccnc2c1c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-4-(piperidin-2-ylmethoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (220 mg, 0.50 mmol) in acetonitrile (2.2 mL) and water (0.45 mL) was added Formalin (41 uL, 1.5 mmol) followed by sodium triacetoxyborohydride (210 mg, 1.0 mmol), and the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (197 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[N:29]1[CH:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31][CH:30]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:35]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)=[O:36])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Reactant: O=C(O)c1cncnc1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3cncnc3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and pyrimidine-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 513.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and naphthalene-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2[C@@H]1CCCNC1
Yield: 85.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (260 mg, 0.52 mmol, 1.00 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (10 mL) was added dropwise with stirring. The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of water. The pH value of the solution was adjusted to >7 with sodium carbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 180 mg (86%) of 3-[4-(3-fluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.