Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]2[N:11](CC3C=C(C)C=C(C)C=3)[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]>C(O)=O.[Pd]>[C:1]([CH:5]1[CH2:10][CH:9]2[NH:11][CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1N2Cc1cc(C)cc(C)c1
Agent: [Pd]
Solvent: O=CO
Product: COC(=O)C1CC2CCC1N2
Yield: 48 %

Procedure:
The product formed in Example 72 was treated with an equal weight of 10% Pd-on-C and refluxed in 96% formic acid for 12 hours. The mixture was filtered, the filtrate was partitioned between 10% aqueous Na2CO3 and methylene chloride, and the extract dried and evaporated, affording a 48% yield of the title compound. Major (endo) isomer: 1H NMR (CDCl3) δ 4.12 (t, 1H), 3.92 (t, 3H), 3.8 (s, 3H), 3.2 (m, 1H), 2.3 (br s, 1H), 2.2-1.55 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:19])=[O:18])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ccccc2C)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 2-methyl-benzenesulfonyl chloride
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichloromethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a pale yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([NH2:50])([C:47](=[O:49])[NH2:48])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:51][C:52]1[CH:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55]>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:42][CH2:43][C:44]([C:47](=[O:49])[NH2:48])([NH:50][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:59]([C:61]([F:62])([F:63])[F:64])=[CH:60][C:52]=2[F:51])[CH2:45][CH2:46]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(C(F)(F)F)cc2F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
HATU (939 mg, 2.47 mmol) and DIPEA (525 μL, 3.09 mmol) were added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.06 mmol) and 2-fluoro-4-trifluoromethyl-benzoic acid (514 mg, 2.47 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 19 hours and then quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was diluted with EtOAc, and the organic layer was then washed with H2O and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was triturated with n-hexane and EtOAc and then collected by filtration to give 4-carbamoyl-4-(2-fluoro-4-trifluoromethyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. This was used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl>[F:23][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CO)cc(C(=O)OC)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(CF)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Under Ar atmosphere, with ice-cooled, to a solution of dimethyl 5-hydroxymethylisophthalate (32) (3.36 g, 15.0 mmol) in CH2Cl2 (150 mL, 0.1 M solution) was slowly added dropwise (diethylamino)sulfur trifluoride (4.00 mL, 30.5 mmol), and stirred for 2 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with MeOH (150 mL). The solvent was removed under reduced pressure. The residue was subjected to extraction with EtOAc and a saturated sodium hydrogen carbonate aqueous solution (three times). The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=10:1) to isolate dimethyl 5-fluoromethylisophthalate (33) (2.57 g, 78%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)COc2ccccc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(COc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(2-phenoxyacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 67.3 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 0.335 g (0.94 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.94 mmol) were used to afford 0.35 g of the required product. Percentage purity (LCMS): 86.8%, (M+1)=553.6 (with BOC). 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (9H, s), 1.82 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 6.74 (1H, d), 6.95 (1H, d), 7.28 (4H, dd), 7.82 (4H, dd), 8.08 (1H, d), 8.21 (1H, d).
Reaction SMILES: CCN(CCN[C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])CC.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1[N:55]=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[N:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:25][C:26](=[O:27])/[C:18]/2=[CH:17]\[C:13]1[NH:14][C:15]([CH3:16])=[C:11]([C:9]([O:46][N:47]2[C:48]3=[N:53][CH:52]=[CH:51][CH:50]=[C:49]3[N:54]=[N:55]2)=[O:10])[C:12]=1[CH3:29]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
15 (10 g, 33.3 mmol) was suspended in DMF (50 ml, 5 P.) and stirred for 5 minutes. DIPEA (9.0 mL, 54.5 mmol) was then added and the mixture was stirred for 10 minutes. HATU (13.95 g, 36.7 mmol) was added and the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight. The intermediate (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (15b) (12 g, 86.5 percent yield) with 86.8% HPLC purity as a yellow powder was got. 1H NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, H-31), 2.68 (s, 3H, H-16), 6.87 (m, 1H, H-2), 7.01 (m, 1H, H-6), 7.64 (m, 1H, H-10), 7.85 (m, 1H, H-3), 8.73 (dd, J=1.5, 1.2 Hz, 1H, H-28), 8.83 (dd, J=1.2, 1.5 Hz, 1H, H-27), 13.11 (s, 1H, NH). To a 15b (10.0 g, 23.9 mmol) DMF solution was added N,N-diethylethane-1,2-diamine (7; 3.33 g, 28.7 mmol), the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight to give Sunitinib (8.38 g, 88% yield) with 77.6% HPLC purity.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K43) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (209 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[CH2:22]([C:21]1[N:32]2[N:33]=[C:29]([CH3:28])[N:30]=[C:31]2[N:34]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[F:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
A mixture of methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (1 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:28][CH:27]=2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 5-bromo-2-oxindole (42 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (80%) of the title compound.
Reaction SMILES: Cl.Cl.[C:3]([NH:11][NH2:12])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:13]([O-])=O.[Na+].C(OCC)C.C(=O)(O)[O-].[Na+]>O>[CH2:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=NCc1cccnc1
Yield: 86.1 %

Procedure:
To a solution of nicotinic acid hydrazide dihydrochloride (2 g) in water (10 ml) was added a solution of sodium nitrite (1.6 g) in water (10 ml), keeping the temperature below 20° C. Diethyl ether (50 ml) was then added and the mixture basified by the careful addition of solid sodium bicarbonate. The organic layer was separated, washed with water (20 ml), dried over anhydrous magnesium sulphate and evaporated to dryness under vacuum to give nicotinyl azide (1.1 g) m.pt. 54° C. This azide (1.1 g) was stirred in dry toluene (10 ml) and heated at 100° C. under a nitrogen atmosphere for 8 hr to give a solution containing 3-pyridyl isocyanate. A portion of this solution (1 ml) was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (100 mg), in toluene (10 ml) at room temperature for 1 hr before pouring into a diethyl ether-water mixture (1:1, 30 ml). The organic layer was separated, dried over anhydrous magesium sulphate and evaporated to dryness under vacuum to give a residue (130 mg) which was purified by high pressure liquid chromatography on a Dynamax (trade mark) column (41.4×250 mm, 8 μm, ODS-silica, Rainin) eluting at 45 ml per minute with a methanol-water 85:15 mixture, changing to 87:13 after 15 mins. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder (52 mg). Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].S(=O)(=O)(O)O.[CH:30](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:30]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: NC=O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.5 g) (prepared by the addition of concentrated sulphuric acid to an ethanolic solution of the free base) and formamide (15 ml) was heated in an oil bath (temp. 190°-200° C.) for 70 minutes. When cool the mixture was filtered and the collected solid was washed with ethanol to give a crude product (1.1 g), m.p. 254°-259° C., which was recrystallised from ethanol to give the title compound, 0.72 g, m.p. 263°-265° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a stirred solution of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol) in CH2Cl2 (80 mL) was added EDC.HCl (13.8 g, 71.8 mmol) followed by 2,2,2-trifluoroethylamine (8.21 g, 82.8 mmol) and 4-(dimethylamino)pyridine (7.31 g, 59.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, taken up in 300 mL of EtOAC, then washed with aq. 10% HCl (3×), aq. 10% K2CO3 (2×) and aq. sat. NaCl (1×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (11.8 g, 84%): mp 166-167° C.; 1H NMR (400 MHz, DMSO-d6) rotamers δ 8.43 (s, 0.3H), 8.20 (s, 0.7H), 7.41 (s, 0.7H), 7.11 (s, 0.3H), 3.84 (dt, J=9.9, 4.9 Hz, 2H), 1.38 (d, J=11.4 Hz, 9H), 1.24 (q, J=4.3 Hz, 2H), 0.92 (q, J=4.3 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −70.57; 13C NMR (101 MHz, DMSO-d6) rotamers δ 172.82, 155.37, 124.64 (q, J=281 Hz), 78.29, 40.18 (q, J=34 Hz), 35.43, 34.70, 28.05, 27.84, 17.28, 16.62.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.C(OCC)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)=CC(=O)O
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-Methyl-2-butenoic acid (1, 5.10 g, 50.9 mmol) and AlCl3 (20.4 g, 153 mmol) were placed in a one-neck round-bottomed flask. Benzene (50 mL) was added, which produced vigorous bubbling. Upon completion of the bubbling, a capped condenser (i.e. closed system) was attached, the reaction mixture was stirred and placed in an oil bath at 65° C. The pressure in the system was occasionally released. The progress of the reaction was followed by following the loss of starting material by GC. If the reaction was not complete within 1 h, a small quantity of AlCl3 was added and stirring was continued. To the solution was added diethyl ether and the mixture was cooled to 0° C. Slowly conc. HCl and some water were added until all the solid dissolved and the pH was less than 2. The aqueous layer was extracted with diethyl ether three times. The organic layer was concentrated to 150 mL and then was extracted with a saturated sodium hydrogen carbonate solution six times. The combined aqueous layer were acidified with conc. HCl until the pH was less than 2. The acidic aqueous layer was extracted with diethyl ether three times and the accumulated organic layer was dried with magnesium sulfate. The solution was filtered and the diethyl ether was removed in vacuo producing a white solid (8.51 g, 47.7 mmol) in 94% yield, which did not need further purification. mp 55-56° C. 1H-NMR (400 MHz, CDCl3) 10.45 (bs, 1H, CO2H), 7.38 (d, 2H, J=7.2 Hz, H-11 and H-7), 7.32 (t, 2H, J=7.2 Hz, H-10 and H-8), 7.21 (t, 2H, J=7.2 Hz, H-9), 2.65 (s, 2H, H-2), 1.47 (s, 6H, H-5 and H-4); Mass spectrum (EI) 178 (23, M.+), 119 (100, [C9H11]+). For pioneering work to form 2 see: F. J. Eijkman (1908) Chem. Kentr. II, p. 110; or A. Hoffman (1929) J. Am. Chem. Soc. 51:2542.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[F:61][C:62]1[CH:70]=[C:69]([F:71])[CH:68]=[CH:67][C:63]=1[C:64](Cl)=[O:65]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([C:64](=[O:65])[C:63]2[CH:67]=[CH:68][C:69]([F:71])=[CH:70][C:62]=2[F:61])[CH2:58][CH2:59]1
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1F)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C31H31ClF2N7O (M+H)+: m/z=590.1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:17][CH:16]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4C(=O)OC[C@H]4C)cc3)CC2)c(C)c1
Yield: 86.6 %

Procedure:
Using (R)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 64 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (212 mg) was obtained.