Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(Cl)Cl.[CH3:10][N:11]1C(C(O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1>CN(C)C=O>[CH3:10][N:11]1[C:1]([C:2]([Cl:4])=[O:3])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)O)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.85 ml) was added to a mixed solution of methylene chloride (5 ml) and N,N-dimethylformamide (5 μl) containing the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (210 mg) obtained in (Example 3.3) <Step 1>, and the obtained mixture was then stirred for 2 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain a crude product (230 mg) of the title compound in the form of an orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NC1CCC(O)c2ccccc21
Reaction time: 5 h
Yield: 11.8 %

Procedure:
To a stirred solution of 4.6 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea in 230 ml of ethanol 0.85 g of sodium borohydride is added. The reaction mixture is stirred for about 5 hours and after standing overnight 50 ml water is added while stirring. The mixture is then evaporated in vacuo to remove the solvent. Water (50 ml) is added, then glacial acetic acid is added, until the foaming caused by the acid ceases. The solution is evaporated to dryness in vacuo, alcohol is added and the whole evaporated to dryness in vacuo. Then 30 ml of ethanol is added to the residue and the mixture stirred and filtered. The collected insoluble solid is air dried. This solid is heated with 300 ml of acetone and filtered. The filtrate is concentrated in vacuo to afford 0.55 g of the title compound, melting point 170°-176° C. On further work-up of the acetone mother liquor, 0.2 g of the title compound, melting point 169°-174° C, is recovered.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:24][CH:25]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CC(C)n1cc(-c2ccc(N)cc2)c2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(NC(=O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Benzoyl chloride (101 mg) in dichloromethane (1.0 ml) was added to a mixture of 4-amino-5-(4-aminophenyl)-7-isopropylpyrrolo[2,3-d]pyrimidine (175 mg), in dichloromethane (7 ml) and triethylamine (73 mg) at 0° C. under nitrogen with stirring. The mixture was stirred at 0° C. for four hours and then allowed to warm up to ambient temperature over one hour. The reaction mixture was stirred at ambient temperature for 18 hours and then quenched by the addition of saturated sodium bicarbonate solution (10 ml) with ice-cooling. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water, dried and evaporated to give a pale yellow solid which was purified by preparative HPLC to give N-(4-{4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-benzamide, m.p. 192-195° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C.C(=O)(O)[O-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Yield: 79.7 %

Procedure:
In a manner similar as described above in Paragraph A, a solution of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine (150 mg, 0.506 mmol) and methyl 4-bromobutanoate (0.29 mL, 2.0 mmol) in THF (6 mL) was treated with triethylamine (0.28 mL, 2 mmol) and the reaction was heated at reflux for 4 hours. The reaction was allowed to cool and treated with an aqueous bicarbonate solution. The combined ethyl acetate extracts were washed with water, dried and concentrated to give 0.16 g of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-butanoate.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:25]=4)[N:20]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:26]1[CH:25]=[C:24]([C:21]2[N:20]=[C:19]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:40])=[O:5])[CH2:18][CH2:17]4)[O:23][N:22]=2)[CH:29]=[CH:28][C:27]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(-c3nc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)no3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCc2cc(-c3nc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)no3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of crude 3-{6-[3-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4]oxadiazol-5-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionic acid tert-butyl ester in CH2Cl2 (1 mL) is added TFA(1 mL). The mixture is stirred at room temperature for an hour. All the solvents are evaporated. The mixture is purified by reverse phase preparative LC/MS to give 3-{6-[3-(2-Trifluoromethyl-biphenyl-4-yl)-[1,2,4]oxadiazol-5-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionic acid: 1H NMR (DMSO, 400 MHz) δ 8.52 (s, 1H), 8.38 (d, 1H), 8.15 (s, 1H), 8.10 (d, 1H), 7.68 (d, 1H), 7.50 (m, 4H), 7.38 (m, 2H), 3.20-3.50 (m, 8H), 2.92 (t, 2H), MS (ES+): (494.10, M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.O1CCCC1CO.O.[NH2:28][NH2:29]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:28][NH2:29])=[O:15])=[CH:12][CH:11]=1
Reactant: COCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: NN
Solvent: O
Solvent: OCC1CCCO1
Product: COCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(6-methoxy-n-hexyloxy)benzoate (17.05 g) in 1:1 tetrahydrofuran-methanol (300 ml) was treated with hydrazine monohydrate (66 ml) and refluxed for 15 hours then cooled to room temperature. The reaction mixture was poured into water and the resulting precipitate collected by filtration, washed thoroughly with water then dried under hi-vacuum at 50° C. to give 4-(6-methoxy-n-hexyloxy)benzohydrazide (15.63 g) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>C(OCC)C>[CH2:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)[CH2:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CC(=O)OC1C=CC(=O)C(C(C)C)O1
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Yield: 92.1 %

Procedure:
In 50 ml of ethyl ether were dissolved 3.96 g of 6-acetoxy-2-isopropyl-2H-pyran-3(6H)-one and 4.84 g of cetyl alcohol with stirring. Into the solution was gradually added 0.1 ml of anhydrous stannic chloride at a temperature of 5° to 10° C. The reaction mixture was stirred at room temperature for 7 hours, washed twice with aqueous sodium hydrogencarbonate solution and once with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 7.0 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one [compound 1] in a yellow viscous oily form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[F:41][C:42]1([F:54])[O:46][C:45]2[CH:47]=[CH:48][C:49](B(O)O)=[CH:50][C:44]=2[O:43]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=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>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:45]4[O:46][C:42]([F:41])([F:54])[O:43][C:44]=4[CH:50]=3)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
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: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OC(F)(F)O4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 85 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g) in 1,2-dimethoxyethane (80 mL) were added 2,2-difluoro-benzo[1,3]dioxole-5-boronic acid (430 mg), 2 M aq. sodium carbonate solution (3.1 mL) and Pd(PPh3)4 (40 mg) and the resulting mixture was stirred at 85° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (1.0 g, 89% yield). HRMS calcd for C37H44O10F2S [M+H]+ 719.2696, observed 719.2693.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[N:18]=2)[CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC1CN(Cc2ccccc2)CCN1c1cncc(Cl)n1

Procedure:
The title compound was prepared according to the procedure of example 39, step 2, starting from the product obtained in step 1 above (4.60 g, 22.5 mmol), 2,6-dichloropyrazine (3.90 g, 26.2 mmol) and K2CO3 (6.22 g, 45.0 mmol). Yield: 6.15 g (86%). MS m/z 316/318 (M)+(35Cl/37Cl-isotope pattern). HRMS m/z calcd for C17H21ClN4 (M)+ 316.1455, found 316.1455.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>C(Cl)(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:20]([NH:19][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:21][N:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)OCc2ccccc2)[nH]n1
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Triethylamine (2.02 g) and benzyloxycarbonyl chloride (1.71 g) were added dropwise to a solution of 3-amino-5-methylpyrazole (971 mg) in chloroform (20 ml) at 0° C., and the mixture was stirred for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 2:1) to give benzyl 5-methyl-2H-pyrazol-3-ylcarbamate (1.65 g, Y.:67%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].O.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Methyl 6-chloro-5-fluoropicolinate (1.35 g, 7.095 mmol) was dissolved in THF:H2O=6:1 (42 ml), followed by addition of lithium hydroxide monohydrate (596 mg, 14.19 mmol), and then the resulting mixture was stirred at room temperature for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, dissolved by addition of distilled water (20 ml), acidified by slow addition of 1N aqueous HCl solution, and then extracted with 5% MeOH/MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 1.04 g of white solid (80%).
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]1[C:12]2[CH2:13][O:14][CH2:15][O:16][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][C:8]=1[CH:19]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=S)[NH2:42])=[CH:37][CH:36]=1)[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[C:31]([NH2:33])=[O:32])[N:21]=1.C(O)(C)C.C[SiH](C)[NH:50][SiH](C)C>C(#N)C>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][CH:19]([C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]3[O:16][CH2:15][O:14][CH2:13][C:12]=3[C:7]=2[F:6])[C:20]2[NH:24][C:23](=[O:25])[N:22]([C:26]3[N:27]=[CH:28][S:29][C:30]=3[C:31]([NH2:33])=[O:32])[N:21]=2)=[CH:40][CH:39]=1)(=[NH:42])[NH2:50]
Reactant: COc1cc(C(Nc2ccc(C(N)=S)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Reactant: C[SiH](C)N[SiH](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CC(C)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(N)=O)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After adding 33 mg of Me3O+BF4− to a suspension of 109 mg of 4-{3-[(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-(4-thiocarbamoylphenylamino)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide in 1 ml of acetonitrile, the mixture was stirred at room temperature for 30 minutes. Next, 4 ml of isopropanol and 0.055 ml of 1,1,3,3-tetramethyldisilazane were added to the reaction mixture, which was then stirred overnight at 60° C. The reaction mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid amide (36 mg).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:34]1([CH2:38][O:39][C:40]2[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[N:42][C:41]=2[N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:37][CH2:36][CH2:35]1.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH:58][C:46]([C:44]1[CH:43]=[N:42][C:41]([N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:40]([O:39][CH2:38][CH:34]2[CH2:35][CH2:36][CH2:37]2)[N:45]=1)=[O:48]
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Reactant: CC(C)CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
A solution of PyBOP (156.1 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 mL) was added to a solution of the 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (62.7 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) and the reaction mixture was left to stand for 20 minutes. 3-methyl butylamine (34.9 mg, 0.4 mmol) and N-ethyldiisopropylamine (103.4 mg, 0.8 mmol) were added and the reaction mixture was shaken for 16 hours. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (3-methyl-butyl)-amide as a solid 35.8 mg (52% yield) LC@215 nm; Rt 2.63: 100%, m/z (ES+): 347 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][NH:6][C:5](=[O:8])C[CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.S(Cl)(Cl)(=O)=O.[CH:21]([Cl:24])(Cl)[Cl:22]>>[Cl:22][C:21]1([Cl:24])[CH2:1][C:2]([CH3:9])([CH3:3])[CH2:7][NH:6][C:5]1=[O:8]
Reactant: ClC(Cl)Cl
Reactant: CC1(C)CCC(=O)NC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC1(C)CNC(=O)C(Cl)(Cl)C1
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) stirred solution of 5,5-dimethyl-2-piperidone (30.2 g, 0.24 mol) in 475 mL of CHCl3, PCl5 (57.1 g, 0.26 mol) was added at such a rate that the temperature never exceeded 7° C. After the addition was complete, stirring was continued for 10 min. Sulfuryl chloride (96.6 g, 0.72 mol) was slowly added and the mixture was heated under reflux for 1 h. The solution was concentrated under reduced pressure. The residue was cooled in ice and diluted with 250 mL of ice-water. The product was then extracted with CHCl3 (6×250 mL) and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, and then the column was eluted with CHCl3-MeOH (50:1). The titled compound was obtained as a white solid (41.3 g, 88.8%). (J. Med. Chem., 20, 1176 (1977))
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH3:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH3:20])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CCI
Product: CCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 37 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.40 g, 1.3 mmol) was reacted with iodoethane to afford 0. 16 g (37%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1C(C(O)=O)=C(C(O)=O)[C:12]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[C:29]([O:32][C:33](=[O:35])[CH3:34])(=[O:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[C:30]2[C:29](=[O:31])[O:32][C:33](=[O:35])[C:34]=2[C:12]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c(C(=O)O)c(OCC(F)(F)F)c2ncccc2c1OCC(F)(F)F
Product: O=C1OC(=O)c2c1c(OCC(F)(F)F)c1cccnc1c2OCC(F)(F)F
Yield: 96 %

Procedure:
A solution of 5,8-bis(2,2,2-trifluoroethoxy)quinoline-6,7-dicarboxylic acid 4 (180 mmol) in acetic anhydride (500 ml) was heated to reflux for 3 h and concentrated to dryness. The solid residue was triturated into 400 ml ether:hexane 1:4 to afford 68.2 g (96% yield for the last two steps) of the anhydride as a brownish solid.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]([OH:32])=O.[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH2:54])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH:54][C:30]([C:25]3[N:26]([CH3:29])[N:27]=[CH:28][C:24]=3[Cl:23])=[O:32])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: Cn1ncc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.5 %

Procedure:
Under an atmosphere of nitrogen, N—N-diisopropylethylamine (121 mg) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 120 mg) were added to a solution of 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.31 mmol, Art-Chem B000148) in DMF (3 ml). After 30 min, 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (110 mg, 0.37 mmol) was added, and the black solution was stirred at r.t. overnight. The reaction mixture was taken up in ethyl acetate and washed with water. After drying (Na2SO4), the solvent was evaporated and the title compound (2 mg, 1.1%) was isolated by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=438.2 [M+H+].
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1>C(OCC)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:3])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (−15° C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at −15° C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.