Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[CH:4]([OH:22])[CH2:3]1.C(N=C=NCCCN(C)C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:44](O)=[O:45])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1.ClCCl>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:44]([O:22][CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]1=2)=[O:45])[CH3:43])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
7-Methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnolin-5-ol (10 mg, 0.03 mmol) obtained in Example 6 was dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (0.5 mL. 0.5 mL), followed by adding N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (9 mg, 0.045 mmol), N,N-dimethylaminopyridine (catalytic amount) and N-(tert-butoxycarbonyl)-L-alanine (9 mg, 0.045 mmol) and stirring at room temperature over night. After completion of the reaction, the reaction liquid was concentrated and thus obtained residue was purified using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[N:12]=[CH:11][N:10]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2ccnc2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.65g, 55% dispersion in oil, pre-washed with petrol) in dry DMF (5ml) at 10-15° C under nitrogen, was added a solution of imidazole (1.02g, 15 mmol) over five minutes. The reaction mixture effervesced and an exotherm took place. After stirring for 11/2hours at room temperature, the cloudy solution was added drop-wise over one hour to a solution of 4,6-dichloropyrimidine in dry DMF (10ml) at 0° C. for one hour, added to water and then extracted with ether (×3). The combined ether extracts were washed with dilute sodium hydroxide solution and water (×3) and then dried. Concentration under reduced pressure gave 4-chloro-6-(imidazol-1-yl)pyrimidine as a pale yellow solid (1.00g); m.p. 122-4° C., which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[C:18]1([C:24]#[C:25][C:26](OCC)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:26](=[O:27])[CH:25]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC(=Nc1ccccc1Cl)c1ccccc1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)c1Cl

Procedure:
To 300 ml of toluene were added 7.4 g (0.030 mole) of 2-chloro-N-(2-chlorophenyl)-1-phenylethaneimine, 5.2 g (0.030 mole) of ethyl phenylpropiolate and 6.7 g (0.050 mole) of aluminum chloride. The reaction mixture was then heated under reflux for 20 hours under nitrogen atmosphere. After cooling, the reaction mixture was poured into 500 ml of 2N sulfuric acid, followed by extraction with chloroform. After washing the organic layer with 50 ml of a 10% aqueous solution of sodium hydroxide and then with water, it was dried with anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) to yield 3-chloro-1-(2-chlorophenyl)-2,6-diphenyl-4(1H)-pyridinone having a melting point of 230°-233° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH:20]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][C:32]3[N:35]=[C:20]([C:14]4[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([O:10][C:7]6[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=6)[CH:12]=5)[NH:16][N:15]=4)[NH:36][C:31]=3[CH:30]=2)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=Cc1n[nH]c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5ccc(Oc6ccc([N+](=O)[O-])cn6)cc45)[nH]c3c2)CC1

Procedure:
The tide compound was synthesized from 5-(5-nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4. LC/MS (m/z) 471.3 (MH+), Rt 2.94 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]2[O:18][C:17](=[O:19])[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a suspension of 3-[(4-t-butylbenzoyl)amino]-2-thiophenecarboxylic acid (8.09 g, 27 mmol) in dry dichloromethane (135 mL) was added oxalyl chloride (11.8 mL, 135 mmol). The mixture was carefully heated with a heat gun in order to dissolve the starting material and initiate the reaction. The heat was then removed and after stirring for 2 h, the solvents were removed in vacuo. The residue was dissolved in dry dichloromethane (135 mL), and pyridine (2.2 mL, 27 mmol) was added. After 1 h, solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was washed four times with water and once with brine. The organic phase was then dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel using an eluent of 10% ethyl acetate in hexane to afford the product (7.44 g, 96% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[NH2:35])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:35][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:19][CH:18]=3)=[O:21])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OCCN1CCCCC1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN1CCCCC1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-piperidin-1-ylethoxy)-4-methoxyaniline (D12) using a similar procedure to Example 1, as a light brown solid (30%) mp 96°-99° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of [(S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.6 g, 4.5 mmol) in DCM (24 mL) was added TFA (12 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to give the crude material as yellow oil (764 mg, 66%) which was used without further purification. LCMS (Method B): RT 1.63 min [M+H]+ 256.9.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:39])=[O:38]
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) and Hunig's base (0.31 mL, 1.8 mmol) is cooled in an ice bath and methanesulfonyl chloride (0.068 mL, 0.88 mmol) is added dropwise. The reaction is stirred cold for 45 minutes and washed with 0.1 N HCl (2×) and H2O. The organic phase is dried (Na2SO4), and concentrated to a white foam. The crude material is purified over silica (1.5% MeOH/dichloromethane) to afford 161 mg (48% yield) of the desired compound. 1H NMR (CDCl3) δ 7.17 (d, J=8.1 Hz, 1H), 7.07 (m, 2H), 7.00 (m, 2H), 6.85 (m, 3H), 4.45 (t, J=8.1 Hz, 1H), 3.96 (t, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.33 (t, J=8.4 Hz, 1H), 3.06 (s, 3H), 2.97 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 2.30 (s, 6H).). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(Cl)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (6.3 9), methyl 3-chloro-5-nitrosalicylate (2.4 g) and triphenylphosphine (10.8 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (6.6 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (3.4 g, yield 79%) as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([Cl:17])=[O:13]
Reactant: O=C(O)CCc1ccc(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:25]([C:26]([NH:28]C(=O)C2C=CC=CC=2)=[S:27])[N:24]=[C:23]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[F:44])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C1COCC1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:25]([C:26](=[S:27])[NH2:28])[N:24]=[C:23]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[F:44])[S:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide (0.677 g, 0.938 mmol) in 20 mL of anhydrous THF was added hydrazine (0.060 mL, 1.87 mmol). The reaction was stirred at room temperature for 3 hours then concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a pale yellow foam, 0.502 g, 87%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11](C(OC(C)(C)C)=O)[CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][N:10]=1)=[O:4]
Reactant: COC(=O)c1ncc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 50.7 %

Procedure:
(+/−)-5-{tert-Butoxycarbonyl-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butyl]-amino}-pyrimidine-2-carboxylic acid methyl ester (1.498 g impure) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added. This was stirred at room temperature. At 70 min, another 3 mL of trifluoroacetic acid was added. At 90 min, the reaction was concentrated and the material was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (0.620 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.16 (s, 2 H) 7.67-7.73 (m, 2 H) 7.61-7.66 (m, 2 H) 7.56 (d, J=8.2 Hz, 2 H) 7.39 (d, J=8.2 Hz, 2 H) 4.68 (d, J=5.7 Hz, 1 H) 4.46-4.57 (m, 1 H) 3.98 (s, 3 H) 1.79-1.92 (m, 1 H) 1.64-1.79 (m, 2 H) 1.05 (d, J=6.2 Hz, 3 H) 0.99 (d, J=6.2 Hz, 3 H); MS (M+1): 444.3.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 94.2 μmol) in dichloromethane (4.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol38), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane added to allow solid formation, light yellow flakes were separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 85.3 μmol, 90.5%). MS (M+H)+=528; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.77-7.98 (m, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.57 (t, J=5.7 Hz, 2H), 3.49 (br. s., 4H), 2.26 (br. s., 6H), 2.00-2.15 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([CH2:4][CH:5]=[CH:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:32])([OH:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCCCOc1ccc(C)nc1/C=C/CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C)[n+]([O-])c1C=CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95 mmol) was dissolved in dry CH2Cl2 (20 mL) and cooled to 0∞C; 85% m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and the reaction was stirred at 0∞C for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into sainted aqueous NaHCO3 (20 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined CH2Cl2 extracts were washed with H2O (20 mL) and brine and dried (MgSO4). The crude pale yellow solid was used directly in the next step without further purification: 1H NMR (250 MHz, CDCl3): δ 8.23 (d, J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8 Hz, 1H, 5- pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6 Hz, 2H, OCH2), 3.81 (s, 3H, CO2CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1.O>C(O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CBr)cc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C)C(=O)OCC
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
Diethyl malonate (183 mg, 1.14 mmol) was dissolved in ethanol (2 mL). Thereafter, sodium ethoxide (78.0 mg, 1.15 mmol) and an ethanol (2 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(bromomethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (390 mg, 0.76 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (300 mg, 67%) in the form of a colorless amorphous product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[O:33][CH3:32])[CH2:45][CH2:44]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.98 (M+H+); retention time=0.95 minutes.