Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH3:32])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH3:32])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-methoxybenzyl (S)-(+)-2-(N-CBz-L-valyloxy)propionate (14.0 g, 31.5 mmole) in dichloromethane (50 ml) was added trifluoroacetic acid (25 ml) and the solution was stirred for five hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 9.4 g=92%
Reaction SMILES: C([O:5][C:6]([C@@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])=[O:7])(C)(C)C.Br>C(O)(=O)C.C(Cl)Cl>[C:6]([C@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])([OH:7])=[O:5]
Reactant: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 4 h

Procedure:
A solution of 15.11 g of the 9:1 mixture from Example 4 in 15 ml of acetic acid was treated at 0° with 15 ml of 33% hydrogen bromide in acetic acid and stirred at 0° for 4 hrs. The solution was diluted with methylene chloride, washed with water and the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml of tert-butyl methyl ether and 26 ml of hexane, after which 6.90 g (70%) of diastereomer-pure (de>98%) 1-[2(R)-[1(R)-carboxy-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX), m.p. 111-114°, was obtained. IR (KBr): 1770m and 1715s (C═O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].[C:16]([O:20][C:21](=[O:28])[NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:25]2[CH2:26][CH2:27][C@H:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[CH2:24]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 74.5 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992; 35(10):1764–1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours. The yellow solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g). 1H NMR (CDCl3): δ 7.35 (ddd, 1H), 4.70–4.65 (bs, 1H), 4.42–4.20 (m, 3H), 3.90–3.62 (m, 3H), 3.58–3.42 (m, 1H), 2.28–2.03 (m, 1H), 1.99–1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[C@H:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[NH2:46][C:33]1[N:32]=[C:31]([O:30][CH3:29])[C:36]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][CH3:21])[CH2:18][CH2:19]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:35][N:34]=1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CO[C@H]1CC[C@H](N2C(=O)c3cc(Br)n(C(C)C)c3[C@@H]2c2ccc(Cl)cc2)CC1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](OC)CC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but (S)-2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(trans-4-methoxy-cyclohexyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AD) and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate U) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light beige solid. tR: 4.08 min (HPLC 1); ESI-MS: tR=0.99 min, [M+H]+ 510/512 (LC-MS 1); TLC: Rf=0.10 (EtOAc).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]([CH3:53])([CH3:52])[CH2:21][NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[N:36][C:37]=3[C:47]3[CH:48]=[N:49][NH:50][CH:51]=3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:24])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[CH3:53][C:20]([CH3:52])([CH2:21][NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[N:36][C:37]=3[C:47]3[CH:48]=[N:49][NH:50][CH:51]=3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:24])[CH2:19][OH:18]
Reactant: C[C@@H](NCC(C)(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NCC(C)(C)CO)c1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-{[teri-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-N-[(1R)-1-{4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]phenyl}ethyl]propan-1-amine (2-5, 0.050 g, 0.070 mmol) in THF (1.0 mL) was added 1M tetrabutylammonium fluoride in THF (0.70 mL, 0.70 mmol) at room temperature and the reaction was stirred at room temperature for 15 hours. The reaction was poured into ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave (2,2-dimethyl-3-{[(1R)-1-{4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]phenyl}ethyl]amino}propan-1-ol (2-6) as a yellow solid. HRMS (M+H)+: calculated 478.2602; found 478.2626.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[C@H:15]1[CH2:19][C@@:18]2([CH2:24][CH2:23][CH2:22][NH:21][C@H:20]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[ClH:1].[CH2:37]([N:21]1[CH2:22][CH2:23][CH2:24][C@:18]2([O:17][CH2:16][C@@H:15]([C:5]3[CH:6]=[C:7]([O:10][C:11]([F:14])([F:12])[F:13])[CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:19]2)[C@@H:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN[C@H]2c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN(Cc3ccccc3)[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R,5R,6S)-3-(2-Methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane hydrochloride (Example 165, 100 mg, 0.2 mmol) and potassium carbonate (38 mg) were dissolved in dimethyl formamide (0.5 mL). Benzyl bromide (0.3 mL) was added and the mixture was stirred at room temperature overnight, then at 60° C. for 3 h. The mixture was cooled, diluted with water (10 mL) and extracted into ether (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (1 M, 1 mL) was added. The solid was collected and dried in vacuo to give the title compound as a crystalline solid (19 mg). 1H NMR (360 MHz, d6 -DMSO) δ 1.75 (3H, m), 2.01 (2H, m), 2.22 (2H, m), 2.96 (1H, m) 3.63 (3H, s), 3.67 (1H, m), 3.92 (1H, m), 4.01 (1H, m), 4.41 (1H, d, J 9.74 Hz), 6.92 (1H, d, J 8.9 Hz), 7.05 (1H, s), 7.13 (1H, d, J 8.65 Hz), 7.31 (2H, d, J 6.53 Hz), 7.42 (3H, m), 7.60 (4H, m), and 7.91 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Temperature: 25 °C
Yield: 148.3 %

Procedure:
Heat a mixture of (3R,4R)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.02 mol, 6.0 g), 5-bromo-2-fluoronitrobenzene (0.03 mol, 6.71 g) and triethyl amine (0.058 mol, 5.88 mL) in ethyl acetate (180 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (12.35 g, crude). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.50-1.51 (m, 1H), 2.08-2.12 (m, 1H), 2.93 (dd, 1H), 3.01 (br s, 1H), 3.55-3.61 (m, 1H), 3.62-3.68 (m, 1H), 3.68 (br s, 1H), 4.13-4.18 (m, 1H), 6.97 (d, 1H), 7.48 (dd, 1H), 8.08 (d, 1H), 8.30 (d, 1H). ES-MS m/z 316 [M−Boc]+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>O>[CH2:12]([N:16]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCN
Solvent: O
Product: CCCCN1C(=O)c2ccccc2C1=O
Temperature: 200 °C
Yield: 95 %

Procedure:
A 10-gallon stainless steel reactor equipped with a turbine blade impeller, cooling coil, distilling condenser, azeotropic separator, thermocouple probe and means to maintain a nitrogen atmosphere, was charged with 15.335 kg (103.53 moles) phthalic anhydride. N-butylamine (7.663 kg, 104.57 moles) from a pressure vessel was slowly added to the reactor which was at room temperature, e.g., about 25° C. The resulting exothermic reaction between the amine and phthalic anhydride was continued until the temperature in the reactor rose to 90° C., at which time addition of amine was complete. The reaction mixture was then heated, with removal of water, for a 5 hour period until the temperature of the mixture reached 200° C. The reaction mixture then was maintained at 200° C. for 2 hours. The resulting product was vacuum distilled at a temperature ranging from 150-155° C. and at a pressure of 20 mm, to afford a liquid which solidified. The melting point of the solid was about 34 to 35° C. and was produced at a 95% yield.
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].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][C:57]([CH3:59])=O>>[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].[CH:57]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)([CH3:59])[CH3:56]
Reactant: CC(C)=O
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(C(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 14 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with acetone (0.13 mL, 10 eq) to provide the title barbituric acid (15.0 mg, 14%). MS found: (M+H)+=502.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH3:23])[CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1
Reactant: CI
Reactant: CCCSc1nc(Cl)ccc1C(=O)NC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)N(C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 116.7 %

Procedure:
6-chloro-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.410 g, 1.3 mmol) in DMF (4 mL) was added portionwise to sodium hydride (60% dispersion in oil) (0.063 g, 1.56 mmol) in DMF (2 mL) cooled to 0° C. over a period of 2 minutes under nitrogen and stirred for 25 minutes. Methyl iodide (0.069 ml, 1.1 mmol) was added in one portion and the suspension was warmed and stirred at 20° C. for 72 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) then diluted with EtOAc (50 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.422 g, 99%) as a colourless clear gum.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][O:31][CH3:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][O:31][CH3:32])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(C)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-(2-methoxyethyl)benzenesulfonamide (Intermediate 15), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[C:3](C(O)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(C(F)(F)F)cnc1Br
Reaction time: 16 h
Yield: 28.7 %

Procedure:
The 3-fluoro-5-(trifluoromethyl)-picolinic acid (7.35 g, 0.035 mole) starting material was put into 150 ml of dry carbon tetrachloride and then red mercuric oxide (9.1 g, 0.042 mole) was added and the mixture was stirred and refluxed 1 hour and 25 minutes. A solution of bromine (6.7 g, 0.042 mole) in 20 ml of dry carbon tetrachloride was added slowly with the mixture at reflux over the next 21/3 hours. Light from a UV lamp was directed on the reaction mixture during the addition and the reaction mixture was refluxed for another hour. 25 Ml more of dry carbon tetrachloride was added and the refluxing was continued for about 16 hours more while UV radiation was applied. The reaction was then filtered through CELITE diatomaceous earth to remove the mercury salt. The carbon tetrachloride was removed on a still and the product was distilled over to yield 2.45 g of yellow oil with an analysis of, in percent by weight:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]=[O:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10].[CH3:33][Mg]Br>O1CCCC1.C(OCC)C>[Cl:32][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]([OH:31])[CH3:33])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(C)O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide (0.1 g, Example 17) in tetrahydofuran (3 ml), at 0° C., was treated with a solution of methylmagnesium bromide in diethyl ether (0.11 ml, 3M). The mixture was allowed to warm to room temperature then stirred for 2 hours. The reaction mixture was quenched with water (15 ml) and then extracted with ethyl acetate (15 ml). The organic extract was dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yield the title compound (68 mg) as a white solid, m.p. 206-211° C. [Elemental analysis:—C, 55.07; H, 4.00; N, 7.92%. Calculated for C23H19Cl2N3O4S:—C, 54.77; H, 3.80; N, 8.33%].
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])=[N+:2]=[N-:3].[C:22]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][O:24][CH2:23]1>ClCCl.O>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([OH:29])=[O:28])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 17-azido-3,6,9,12,15-pentaoxaheptadecanamine (15 g, 50 mmol) in dichloromethane (100 mL) was added diglycolic anhydride (Acros, 6.4 g, 55 mmol). The reaction mixture was stirred overnight. The reaction was monitored by ESI-MS analysis, and more reagents were added to drive the reaction to completion. The solution was concentrated to give a yellow residue which was dissolved in water (250 mL). The product was isolated from the aqueous phase by continuous extraction with dichloromethane over night. Drying and evaporation of the solvent gave a yield of 18 g (85%). The product was characterized by ESI-MS analysis (MH+ calculated: 423.20; found 423.4). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=C)=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:25])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C=O
Reaction time: 0.03 h
Yield: 96.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid methyl ester (0.500 g, 1.5 mmol) was dissolved in THF (3 mL) and water (3 mL). Osmium tetroxide (4 mg, 0.015 mmol) was added and the reaction mixture was stirred for 2 min. Sodium periodate (0.63 g, 3 mmol) was then added over a period of 2 min. The reaction mixture was stirred for 16 h at ambient temperature then poured into water (150 mL) and extracted with dichloromethane thrice. The combined organic layers were dried, filtered and concentrated to afford the title compound (490 mg, 98% yield) in sufficient purity for subsequent reactions. An analytical sample was obtained by reverse phase chromatography: 1H NMR (CDCl3) δ 10.31 (s, 1H), 8.72 (br s, 1H), 7.77 (dd, 1H), 7.23 (m, 1H), 6.03 (br s, 1H), 4.06 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:2][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][CH2:13][CH2:12][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH2:16][CH2:17]1
Reactant: c1cn[nH]c1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccn3)CC2)nc1
Temperature: 140 °C

Procedure:
A mixture of 730 g (3.59 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 275 g (4.05 moles) of pyrazole and 745 g (5.4 moles) of potassium carbonate in 3 1 of dimethylformamide is heated to 140° C. for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 650 g (94%) of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained in liquid form.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([O:27]C)=[O:26])[C:12](=[O:29])[C@H:11]1[CH2:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O.C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([OH:27])=[O:26])[C:12](=[O:29])[C@H:11]1[CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CN1C(=O)[C@@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@H]1CC1CCCCCC1

Procedure:
24 mg (1.3 mmol) lithium hydroxide in 1.0 ml of water were added to 0.55 g (1.1 mmol) (2R)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (isomer 4.1.1) in 5 ml THF. After 2 h at RT the mixture was neutralised with 0.1 M hydrochloric acid solution. The reaction mixture was evaporated to dryness by rotary evaporation.