Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:9][OH:10]>F[B-](F)(F)F.C[N+](C)(C)C>[CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:10][CH3:9])=[O:2]
Reactant: O=CN1CCCCC1
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCN1C=O
Yield: 94.2 %

Procedure:
In the flow apparatus with cell as described in Example 1 a mixture of 4,800 g of 1-formylpiperidine, 13,600 g of methanol and 68 g of tetramethylammonium tetrafluoroborate was electrolyzed at 27.5 A, 42 volts and 25° C. for 27 hours and 33 minutes (corresponding to 2,273 Ahr). After distillative work up, 5,720 g of 1-formyl-2-methoxypiperidine were isolated, corresponding to a current efficiency of 86.9%.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:29]=2[Cl:38])[CH2:18][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:8]=1)([CH3:6])[CH3:5].[Li+].[Cl-]>CN(C=O)C>[ClH:38].[Cl:38][C:29]1[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:17]([CH2:18][C@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:16][CH2:15][CH2:14][O:13][C:9]1[CH:8]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:39])=[O:2])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C[C@H](CN(CCCOc1cccc(C(C)(C)C(=O)O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of 2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionic acid methyl ester (30 mg, 0.05 mmol) in DMF (9 ml) was treated with LiCl (20 mg, 0.46 mmol). The resulting reaction mixture was heated to reflux overnight and concentrated under vacuum. The crude product was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give the title compound free amine as an oil (15 mg, 45%). MS m/e 548.2(M+H)+. To a solution of the free amine in diethyl ether was added HCl in diethyl ether (1.0M) to precipitate the amine salt. The suspension was filtered and dried to give the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]([O:12][C:13]([NH:15][C@H:16]([CH2:25][OH:26])[CH2:17][C:18]([O:20][C:21](C)(C)[CH3:22])=[O:19])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([O:12][C:13]([NH:15][C@H:16]([CH2:25][OH:26])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[O:20]=[C:18]1[O:26][CH2:25][C@@H:16]([NH:15][C:13](=[O:14])[O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Reaction time: 0.5 h
Yield: 32 %
Yield: 56 %

Procedure:
To ethanol (188 ml, 3.24 mol) was added at 0° C. acetyl chloride (46 ml, 0.65 mol). The mixture was stirred at the same temperature for 30 minutes and added to tert-butyl(3S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxybutanoate (10.0 g, 32.3 mmol) in ethanol (20 ml). The mixture was stirred overnight. After removal of the solvent, the residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give ethyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxybutanoate (2.92 g, 32%) with a lactone compound, benzyl (3S)-5-oxotetrahydro-3-furanylcarbamate (4.24 g, 56%) as by-product.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.S([O-])([O-])(=O)=[O:38].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:38])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)([O-])[O-]
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(Cc2ccccn2)C[C@@H]1CCCB(O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and pyridine-2-carboxaldehyde (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylic acid (141 mg, 74%) as a white solid. NMR (D2O) δ 8.63 (m, 1 H), 8.20 (m, 1 H), 7.65-7.85 (m, 2 H), 4.50-4.65 (m, 2 H), 3.86 (d, J=12.5 Hz, 1 H), 3.70 (m, 2H), 3.22 (t, J=11 Hz, 1H), 2.55 (m, 1 H), 1.55 (m, 1 H), 1.15-1.35 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 308.0; MS (m−H2O+1): 290.2.
Reaction SMILES: C(OC([CH:8]1[CH2:13][CH2:12][C:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=O)(C)(C)C.Br[CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[N:30]=[C:29]([Cl:34])[CH:28]=1.[I-].[K+].[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:11]([O:38][C:37]([N:9]1[CH:10]=[C:11]([C:14]2([CH2:26][C:27]3[CH:32]=[C:31]([Cl:33])[N:30]=[C:29]([Cl:34])[CH:28]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:12][CH2:13][CH2:8]1)=[O:40])([CH3:14])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)C1CCC(C2C(=O)Nc3cc(Cl)ccc32)=CN1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(CBr)cc(Cl)n1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C=C(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CCC1
Temperature: 60 °C

Procedure:
A mixture of 5-[6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (0.32 g, 0.9 mmol) (from Example 20a supra), 4-bromomethyl-2,6-dichloro-pyridine (0.26 g, 1.08 mmol) (Maybridge), potassium iodide (0.18 g, 1.08 mmol) and potassium carbonate (0.27 g, 1.97 mmol) in acetone (30 mL) was heated at 60° C. for 2 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 25:75, V/V) to give rac-5-[6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white solid. (Yield 0.28 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N#N.[Li]CCCC.[CH2:39]=[O:40]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH2:39][OH:40])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A solution of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (650 mg, 1.5 mmol) in THF (20 mL, dry) was cooled to −78° C. and protected with N2. Another solution of n-BuLi (1.5 M, 3 mL, ˜4.5 mmol) in THF was added to the above cooled solution during 5 min. The reaction mixture was stirred at −78° C. for 1 h, followed by the addition of paraformaldehyde (405 mg, 15.0 mmol) in one portion under −78° C. This solution was stirred at RT overnight. The reaction was quenched by saturated aqueous NH4Cl (50 mL) and water (50 mL), and extracted with EtOAc (50 mL*4). The combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EA (4:1) to obtain the title compound as a yellow thicky oil (300 mg, 44% yield). MS (ES+) C23H29FN4O5 requires: 460. found 461 [M+H]+; purity: 93% (UV214).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:24])[CH:3]=1.C([O-])(=O)C.[NH4+].CN1CCCC1=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:7])[C:8]3[C:9]([C:18]([F:19])([F:20])[F:21])=[N:10][NH:11][C:12]=3[C:13](=[O:15])[NH:24][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(C(F)(F)F)n[nH]c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Alternatively, the title compound can be preferably prepared as follows: A mixture of ethyl 4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (1.0 g, 2.76 mmol), ammonium acetate (0.21 g, 2.76 mmol) and 1-methyl-2-pyrrolidinone (2.3 mL) was heated with stirring at 160° C. under N2 for one hour. After cooling to room temperature, water (25 mL) was added to the stirred reaction mixture. The resulting aqueous mixture was filtered after stirring for ten minutes. The filter cake was washed with water (2×25 mL) then dried under vacuum to give a tan solid. The solid was placed in methylene chloride (25 mL) and the mixture was stirred for fifteen minutes, then filtered. The filter cake was washed with methylene chloride (2×25 mL) and dried under vacuum to give the title compound as a tan solid (0.66 g, 76%, m.p. 334-336° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(Cl)Cl.CO>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Cc2ccncc2)nnc(Nc2cccc(Cl)c2)c1C
Temperature: 30 °C

Procedure:
The compound is prepared starting from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.153 g meta-chloroaniline in the manner described in Example 82A. After heating for 20 h to 1 30° C., siginificant quantities of 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine are still present (TLC). For this reason, a further 0.153 g meta-chloroaniline is added and heated for another 24 h to 1 30° C. Processing is in the manner described for Example 82A. Title compound is obtained after FC in CH2Cl2/methanol 19/1: m.p. 164-167°. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.70 (t, 1H); 7.45 (dd, 1H); 7.25-7.10 (m, 3H)); 7.00 (dd, 1H); 6.20 (s, wide, 1H); 4.25 (s, 2H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 325, 327 (M+H for 35Cl and 37Cl).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([O:13][CH3:14])[C:10](Cl)=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][NH:25][C:24]2=[O:29])[CH:19]=[C:20]([Cl:22])[CH:21]=1>O1CCCC1>[CH3:14][O:13][N:9]([CH3:8])[C:10]([N:25]1[CH2:26][C:27](=[O:28])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:24]1=[O:29])=[O:11]
Reactant: CON(C)C(=O)Cl
Reactant: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 20 °C

Procedure:
At about 20° C, 10.5 parts of triethylamine and subsequently 12.4 parts of methylmethoxycarbamoyl chloride are added to a suspension of 24.5 parts of 3-(3,5-dichlorophenyl)-hydantoin in 250 parts of dry tetrahydrofuran. After all has been added, the mixture is refluxed for 3 hours. After the mixture has been cooled to 20° C, the precipitated triethylamine hydrochloride is removed by suction filtration. The filtrate is concentrated. The residue is dissolved in a 1:1 mixture of n-pentane and ether, suction filtered, dried and recrystallized from toluene.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH3:11])=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cn1ccc(C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccn(CC(=O)NN)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (3-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. The mixture was then cooled to rt and the precipitated product was filtered off and crystallized from ethanol. The title compound (>95% purity) was obtained as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.12 (s, 3H), 4.29 (s, 2H), 4.60 (s, 2H), 6.00 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.C([O:17][C@@H:18]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[CH2:29][S:28][C@H:19]1[O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](Br)[CH:26]=1)(=O)C>>[O:20]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:26]=1)[C@@H:19]1[S:28][CH2:29][C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:18]1[OH:17]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)c(OC)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2,4-dimethoxyphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2,4-dimethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=71%).
Reaction SMILES: N1C=C(CCN)N=C1.[CH:9]1[N:13]=[CH:12][N:11]([C:14]([N:16]2C=N[CH:18]=[CH:17]2)=[O:15])[CH:10]=1>CN(C=O)C>[CH:9]1[N:13]=[CH:12][N:11]2[C:10]=1[CH2:18][CH2:17][NH:16][C:14]2=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NCCc1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1NCCc2cncn21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(1H-imidazol-4-yl)ethanamine (26.8 g; 240.9 mmol; 1 eq) and CDI (39.1 g; 240.9 mmol; 1 eq) in DMF (402 ml) is stirred at 50° C. for two days. Solvents are concentrated to 100 ml and acetonitrile (200 ml) is added. The resulting precipitate is filtered, washed with acetonitrile (2×50 ml) and dried under vacuum, affording the title compound that is used in the next step without further purification (28.18 g; 85%).
Reaction SMILES: [CH:1]([N:4]([C:6]#[N:7])[NH2:5])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:10]([SH:12])[CH3:11].[C:13](Cl)(Cl)=[O:14]>O>[CH:1]([N:4]1[C:6]([S:12][CH2:10][CH3:11])=[N:7][C:13]([OH:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)N(N)C#N
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSc1nc(O)nn1C(C)C
Temperature: 25 °C

Procedure:
19.8 g (0.2 mole) of 1-isopropyl-1-cyanohydrazine is added dropwise to a solution of 16.0 g (0.4 mole) of sodium hydroxide and 12.4 g (0.2 mole) of ethyl mercaptan in 75 ml of water. Into the resulting white emulsion there is then introduced 19.8 g (0.2 mole) of phosgene at room temperature, and an exothermic reaction occurs. The reaction mixture cooled to room temperature, from which has separated out a white-yellow precipitate, is extracted with methylene chloride and the extract is dried with sodium sulphate. After removal of the methylene chloride by evaporation in vacuo, the crude product is purified by dissolving it in 50 ml of methanol, treating the solution with animal charcoal and crystallising the resulting product at -50° C. There is obtained 1-isopropyl-3-hydroxy-5-ethylthio-1,2,4-triazole, m.p. 109°-114° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH3:38][CH:39]([OH:52])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[CH3:38][CH:39]([O:52][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCC(C)O
Product: CCCCCCCCCCCCC(C)OC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 1-methyl-tridecanol.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.FC1C=NN(C)C=1C(O)=O.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.[NH:54]1[C:62]2[C:57](=[C:58]([C:63]3[CH:64]=[C:65]([NH2:72])[C:66]4[CH:67]=[N:68][NH:69][C:70]=4[CH:71]=3)[CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55]1>CN(C=O)C.CO>[F:1][C:2]1[C:3]([C:8]([NH:72][C:65]2[CH:64]=[C:63]([C:58]3[CH:59]=[CH:60][CH:61]=[C:62]4[C:57]=3[CH:56]=[CH:55][NH:54]4)[CH:71]=[C:70]3[C:66]=2[CH:67]=[N:68][NH:69]3)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(F)c(C(=O)O)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cn1ncc(F)c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(F)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 4-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid and 4-fluoro-1-methyl-1H-pyrazole-5-carboxylic acid (45:55) (580 mg, 20% W/W), HATU (306 mg), and DIPEA (0.422 ml) in DMF (3 ml) was stirred at RT for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (100 mg) in DMF (3 ml) was then added and the mixture was stirred at RT overnight. The reaction mixture was added to a 20 g aminopropyl SPE cartridge which had been preconditioned with methanol. The reaction mixture was allowed to remain on the cartridge for 3 h before being eluted with methanol (4 column volumes) and then 10%-triethylamine in methanol (6 column volumes). The appropriate fractions were evaporated to give a brown oil which was partitioned between ethyl acetate (25 ml) and water (5 ml). The phases were separated and the organic phase was dried over anhydrous sodium sulphate and evaporated to a brown oil. This was dissolved in ethyl acetate (10 ml) and pre-adsorbed on silica (1.2 g) which was then added to the top of a 20 g silica SPE cartridge. The cartridge was eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 60 min to give the title compound (65 mg) as a buff-coloured solid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:18][CH2:19][N:20]3[CH:25]4[CH2:26][CH2:27][CH:21]3[CH2:22][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:24]4)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)[CH3:4].C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[CH3:45][C:46]([CH3:51])([CH3:50])[C:47]([N:15]1[CH2:16][CH2:17][C:12]([CH2:18][CH2:19][N:20]2[C@H:21]3[CH2:27][CH2:26][C@@H:25]2[CH2:24][CH:23]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[CH2:22]3)([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:3][CH3:4])[CH:7]=2)[CH2:13][CH2:14]1)=[O:48]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOc1cccc(C2(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cccc(C2(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)CCN(C(=O)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 1-(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1:9 methanol:dichloromethane gradient to give 1-((1R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.14 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.28 (m, 2H), 7.16 (m, 2H), 6.86 (m, 2H), 6.76 (m, 1H), 4.63 (m, 1H), 4.04 (m, 2H), 3.94 (m, 2H), 3.29 (m, 4H), 2.59 (s, 3H), 2.40 (m, 2H), 2.19 (m, 2H), 1.66-1.95 (m, 12H), 1.43 (t, 3H), 1.26 (s, 9H). HRMS C35H48N4O2 m/z 557.3856 (M+H)Cal., 557.3840 (M+H)Obs..
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[ClH:20].[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:33]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: COC1CCCNC1
Product: COC1CCCN(CCOc2ccc3oc(-c4cc5cccn5cn4)cc(=NO)c3c2)C1
Product: Cl

Procedure:
6-[2-(3-methoxy-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 37% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 3-methoxy-piperidine.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:6](=[O:10])([OH:9])([OH:8])[OH:7].[Zr:11]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[Zr+4:11]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Agent: O=P([O-])([O-])[O-]
Product: [Zr+4]
Temperature: 350 °C

Procedure:
A zirconium phosphate film was prepared by adding a stoichiometric amount of phosphate in the form of phosphoric acid to a solution of zirconium bound to PEI. The solution was then spin coated onto a glass slide and thermally treated at 1° C. to 120° C. with a dwell time of 30 minutes followed by heating to 350° C. at 1° C./minute with a dwell time of 30 minutes followed by heating to 450° C. at 1° C./minute with a dwell time of 1 hour and then cooling to 25° C.