Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[C:43]([C:44](O)=[O:45])=[CH:42][N:41]=[CH:40][CH:39]=1.C([O-])(=O)C.[NH4+]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:44]([C:43]3[CH:42]=[N:41][CH:40]=[CH:39][C:38]=3[CH3:37])=[O:45])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ccncc1C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 79 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 4-methyl-nicotinic acid in 79% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.22 (d,3H), 1.36 (s,3H), 2.10 (d,1H), 2.40 (m,1H), 2.62 (m,1H), 2.99 (d,1H), 3.22 (m,1H), 3.94 (m,2H), 4.23 (m,1H), 7.26 (d,1H), 7.90 (s,1H), 8.16 (d,1H), 8.23 (s,1H), 8.34-8.46 (m,3H), 9.02 (s,1H), 10.04 (s,1H), 11.27 (s,1H). Retention Time (LC, method: ammonium acetate standard): 2.22 min.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.IC.[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33][CH3:1])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:17][CH2:18]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Solvent: CI
Solvent: ClCCl
Product: COC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.0 ml of iodomethane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172) in 50 ml methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.38 g of N-(trans-4-methylcyclohexyl)4-(methoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][NH:11][C:10]1=[O:24])=O)(C)(C)C.C[Si](I)(C)C.O>C(Cl)Cl.CO>[NH2:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19])[CH2:12][NH:11][C:10]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)NC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
(3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one (8.0 g, 22 mmol) is dissolved in 40 mL of CH2Cl2 and cooled to −78 ° C. Trimethylsilyl iodide (3.5 mL, 24.5 mmol) is added slowly. The mixture is allowed to react at −78 ° C. for 30 min. The reaction is warmed to 0° C. and stirred for 15 min. The solution turned yellow. The reaction is quenched with NH4HCO3 (3.43g, 44 mmol) dissolved in 30 mL of CH3OH, and 15 mL water. The mixture is concentrated and chromatographed with 95:5 mixture of CH2Cl2 and methanol to yield 5.45 g (96%) of (3S, 6R)-3-aminohexahydro-6-tert-butyl-dimethylsilyloxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3) δ 5.61 (s, 1H), 3.88 (s, 1H), 3.42 (d, J=8 Hz, 1H), 3.32 (dd, J=6 Hz and 16 Hz, 1H), 3.06 (m, 1H), 1.87 (m, 2H), 1.76 (m, 1H), 1.65 (s, 3H), 0.83 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>C(O)C>[C:1]([N:5]1[C:17]([NH2:18])=[C:14]([C:15]#[N:16])[CH:13]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CCOC=C(C#N)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ncc(C#N)c1N
Yield: 87.5 %

Procedure:
To a mixture of tert-butylhydrazine (40 g, 0.32 mol), sodium methoxide (18 g, 0.32 mol) and ethanol 150 ml) was added ethoxymethylene malononitrile (42 g, 0.32 mol). The reaction mixture was heated to reflux for 2 hours and the solvent was removed in vacuo. The residue was extracted with chloroform, washed with water and the organic layer was concentrated in vacuo to afford 46 g (87%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as a semi-solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[H-].[Na+].[Cl:21][C:22]1[C:23]([F:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.[NH2:31][OH:32]>CN(C=O)C.CO.O>[Cl:21][C:22]1[C:23]([F:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([NH:31][OH:32])=[O:16])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: Fc1c(Cl)cccc1CBr
Reactant: NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(NO)c1cc2c3ccccc3n(Cc3cccc(Cl)c3F)c2cn1
Reaction time: 25 h
Yield: 31 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (400 mg, 1.66 mmol) in DMF (5 mL) under nitrogen atmosphere was added NaH (66.4 mg, 60% in mineral oil, 1.66 mmol) portionwise, followed by 3-chloro-2-fluoro-benzyl bromide (371 mg, 1.66 mmol). Stirring was continued for 25 hours at ambient temperature, water (30 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (25 mL). To the resulting solution, H2NOH (25 mL, 50 wt. % solution in H2O, 0.38 mol) was added. The suspension was stirred for 4 days at ambient temperature. The mixture was then filtered, and the solid was boiled in methanol (20 mL). After filtration, the title product (0.19 g, 31%) was obtained. 1H NMR (400 MHz, DMSO-d6): δ 11.33 (1H, s), 9.08 (1H, s), 9.04 (1H, s), 8.89 (1H, s), 8.51 (1H, d, J=8 Hz), 6.95–7.81 (6H, m), 6.00 (2H, s). HRMS (M+H)+ found: 370.0764. Calcd for C19H14N3O2FCl: 370.0759.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9].CCO.Cl>O>[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)COc1ccc(-c2ccco2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(-c2ccco2)cc1Cl

Procedure:
0.40 g (10.00 mmol) NaOH in 5 mL water was added to a solution of 0.280 g (2.672 mmol) ethyl (2-chloro-4-furan-2-yl-phenoxy)-acetate (130a) in 20 mL abs. EtOH and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water and acidified to pH 1 with semiconc. aqueous HCl. The precipitate was filtered off, washed with water and dried in a HV.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[O:24])[C:5]1=[O:32])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCOC(C)C)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(1-methylethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.021 g, 0.046 mmol) and diisopropyl ethylamine (0.04 mL, 0.23 mmol) in DMF (5 mL) under nitrogen was treated with acetic anhydride (0.0046 mL, 0.048 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was treated with 1 N NaHSO4. Extracted the mixture twice with EtOAc, combined the organics, dried over MgSO4, filtered and concentrated the filtrate. The residue was then triturated with Et2O, filtered, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.0 Hz, 6 H), 1.7 (s, 3 H), 3.3 (q, J=6.1, 2 H), 3.5 (m, 3 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (t, J=6.5 Hz, 2 H), 7.1 (m, 2 H), 7.4 (ddd, J=12.1, 5.5, 3.2 Hz, 2 H), 8.0 (d, J=6.0 Hz, 1 H), 8.2 (d, J=1.3 Hz, 1 H), 8.5 (d, J=1.5 Hz, 1 H), 10.4 (t, J=5.1 Hz, 1 H), 17.1 (s, 1 H); ES+ MS: 485 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=[O:30]>[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:30][CH:4]1[CH2:3][N:2]([CH3:1])[CH:11]2[C:10]3[C:5]1=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[C:9]=3[C:18]1[C:13]([CH2:12]2)=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2C)cc1OC
Agent: O=[V]([O-])([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)N(C)CC3O

Procedure:
2 g. (+)-laudanosine (Eur. J. Med. Chem., 9, 237/1974) is reacted, in the manner described in Example 1, with 1.73 g. vanadyl (V) fluoride in trifluoroacetic acid. After analogous working up and crystallisation from diethyl ether, there is obtained (+)-4-hydroxy-1,2,9,10-tetramethoxyaporphine (cataline) in the form of colourless crystals; m.p. 180° - 182° C.;
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:36]=[CH:35][C:19]2[NH:20][C:21]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[CH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:36]=[CH:35][C:19]3[NH:20][C:21]([CH2:23][O:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)=[N:22][C:18]=3[CH:17]=2)[CH:8]([CH3:9])[O:44]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1OC1(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of 5-{2-[1-(tert-butyl-dimethyl-silanyloxy)-propenyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.052 g, 0.0965 mmol) in CH2Cl2 (4 mL) at rt was added m-chloroperoxybenzoic acid (77% max, 0.035 g, 0.154 mmol). After stirring for 2 hours, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.050 g, 94%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]
Reactant: Cc1ccc(NC(=O)c2ccc(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Oc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 86E (305 mg, 0.504 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 1 hour at which time the solvent was removed on the under vacuum. The resultant residue was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (35 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 2.28 (s, 3 H), 3.28 (qt, J=13.70, 6.94 Hz, 1 H), 6.82-6.88 (m, 2 H), 6.91-6.99 (m, 3 H), 7.16 (d, J=8.46 Hz, 2 H), 7.63 (d, J=8.46 Hz, 2 H), 7.86 (d, J=8.46 Hz, 1 H), 7.98 (dd, J=8.46, 2.21 Hz, 1 H), 8.13 (d, J=2.21 Hz, 1 H), 8.87 (s, 1 H), 8.98 (d, J=8.46 Hz, 1 H), 10.17 (s, 1 H); MS (ESI+) m/z 505 (M+H-TFA)+; (ESI−) m/z 503 (M−H-TFA)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].N[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35].C[N:37]1C(=O)CCC1>>[NH2:37][C:33]1[CH:32]=[CH:31][C:30]([S:35][C:2]2[CH:3]=[C:4]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:29][CH:34]=1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Reactant: Nc1ccccc1S
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Product: N#CC1(c2cccc(Sc3ccc(N)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
4-(3-Bromo-phenyl)-tetrahydro-pyran-4-carbonitrile (133.4 g), Na2CO3 (363.6 g), Cs2CO3 (223.1 g) and aminothiophenol (62.8 g) were heated in N-methyl pyrrolidinone (2.3 L) at 130° C. for 24 hours. More aminothiophenol (35.6 g) was added and heating was continued for another 8 hours. The mixture was cooled to room temperature, poured onto icewater (6.8 L) and filtered off. The product was suspended in water (2.5 L) filtered again and washed with water (1.5 L). The product was then slurried in EtOH (0.5 L), filtered off and dried at 40° C./20 mbar to yield 4-[3-(4-Amino-phenyl sulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (134.3 g, 86%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)nc3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cn2)CC1

Procedure:
The title compound was synthesized from 5-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)picolinic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.04 (m, 13H) 2.77 (d, J=5 Hz, 2H) 3.01-3.22 (m, 2H) 3.34 (s, 3H) 3.47 (d, J=11 Hz, 2H) 4.08 (m, 3H) 4.80 (m, 1H) 7.85-8.02 (m, 1H) 8.30 (s, 1H) 8.44 (dd, J=9, 2 Hz, 1H) 8.69 (d, J=8 Hz, 1H) 8.80-8.92 (m, 1H) 9.85-10.01 (m, 1H). [M+H] calc'd for C25H32F2N8O2, 516. found 516.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[C:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>N1C=CC=CC=1>[C:1]([O:18][C:16]1[CH:17]=[C:12]([F:11])[C:13]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[N:14][CH:15]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCCCCCC)cc2F)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at O° C. to 1.5 g (4.7 mmol) of 3-fluoro-5-hydroxy-2-(4octyloxyphenyl)pyridine in 20 ml of pyridine and the mixture is stirred at 0° C. for 3 hours, subsequently poured into ice-water and filtered and the residue is purified by chromatography (silica gel/hexane: ethyl acetate 9:1) and by recrystallization from acetonitrile, giving 1.34 g of 3-fluoro-2-(4-octyloxyphenyl)pyridin-5-yl octanoate. ##STR20##
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](O)=[O:14])[C:10]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([N:40]2[CH2:39][CH2:38][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:14])[C:10]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C1CN(Cc2ccccc2)CC12CCCc1ccccc12)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylic acid (0.1 g, 0.311 mmol) in CH2Cl2 (4 ml) was added oxalyl chloride (0.187 ml, 0.373 mmol) followed by 2 drops of DMF. Stirred at room temperature for 30 minutes and concentrated. Dissolve in THF (5 mL) and added 4-phenylpiperidine (0.050 g, 0.311 mmol) and triethylamine (0.173 ml, 1.245 mmol).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14](Cl)[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14]([NH:2][NH2:3])[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=c1c(Cl)nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Hydrazine hydrate (2.7 ml, 55 mmol) was added to a solution of 5.9 g (14 mmol) of 1-benzyloxy-3-chloro-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in 100 ml of dichloromethane with stirring at 0° C. After 1 h the mixture was evaporated to dryness and the residue was triturated with water and dried to give 5.3 g (90%) of crude title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])C=C.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][CH:8]=[CH2:9]>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCl>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][CH:8]=[CH:9][C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: C=CCCOC1CCCCO1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=C(O)C=CCCOC1CCCCO1
Yield: 84 %

Procedure:
In a 500 ml rb flask were placed acrylic acid (2.85 g, 39.6 mmol) and Grubbs catalyst (1.68 g, 1.98 mmol) in anhydrous dichloromethane (200 ml). To this solution was added 2-but-3-enyloxy-tetrahydro-pyran (7.73 g, 49.50 mmol) and heated at refluxing for 12 hrs. The solvent was removed and the residue was purified on the column with Hexane/Ethyl acetate=100/5 to remove unchanged 2-but-3-enyloxy-tetrahydro-pyran. Then the column was eluted with Ethyl acetate/Methanol=100/1 to provide 6.66 g of a black oil (84%). 1H-NMR (DMSO-d6) δ 12.190 (s, 1H), 6.845-6.771 (m, 1H), 5.846-5.800 (d, 1H), 4.565-4.548 (t, 1H), 3.739-3.674 (m, 2H), 3.468-3.398 (m, 2H), 2.481-2.395 (m, 2H), 1.689-1.609 (m, 2H), 1.501-1.259 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:14]=4[N:13]([CH3:20])[C:12]=3[C:21]([OH:23])=O)=[C:6]([F:24])[CH:5]=2)[CH2:3][CH2:2]1.[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].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>C1COCC1>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:21]([C:12]1[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:24])=[O:23])=[CH2:26]
Reactant: Cn1c(C(=O)O)c(Nc2ccc(C3CC3)cc2F)c2cnccc21
Reactant: C=COCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1c(Nc2ccc(C3CC3)cc2F)c2cnccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A suspension of 3-(4-cyclopropyl-2-fluoro-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (88 mg, 0.25 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (028 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (0.052 ml, 0.30 mmol) in THF (3 ml) was stirred at ambient temperature for 18 hours. On completion of the reaction, the mixture was concentrated in vacuo then re-dissolved in DCM. The solution was washed with saturated aqueous NaHCO3 and brine, dried over magnesium sulphate then concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10) to give a yellow solid (34 mg, 33%). LCMS (method B): RT=2.46 min, M+H+=411. 1H NMR (CDCl3): 8.58 (1H, s), 8.41-8.36 (1H, m), 7.30 (1H, d, J=6.08 Hz), 7.26 (1H, d, J=1.99 Hz), 6.87 (1H, dd, J=8.33, 2.02 Hz), 6.47 (1H, dd, J=8.34, 3.82 Hz), 5.85 (1H, s), 4.11 (3H, s), 3.97-3.90 (2H, m), 3.71 (2H, dd, J=5.23, 3.41 Hz), 2.78 (1H, m), 1.22-1.13 (6H, m).