Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:13][C:12]1[C:7]([NH:33][CH:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: NC1CCCc2ccccc21
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCc3ccccc32)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1,2,3,4-tetrahydronaphthalen-1-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 3H), 1.83 (bs, 4H), 2.09 (s, 3H), 2.66-2.75 (m, 2H), 4.46 (d, J=5.37 Hz, 2H), 5.31 (bs, 1H), 6.33 (d, J=8.33 Hz, 1H), 6.70-6.78 (m, 1H), 7.07 (dd, J1=15.31 Hz, J2=6.45 Hz, 4H), 7.15 (d, J=5.64 Hz, 1H), 7.26 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.25 Hz, 1H), 8.42 (d, J=4.03 Hz, 1H); MS (ESI) m/z 361.0 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][CH2:5]Cl.[CH:7]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[N+:8]([O-:10])=[O:9].[K]>>[Br:1][CH2:2][CH2:3][O:4][CH2:5][C:7]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[N+:8]([O-:10])=[O:9]
Reactant: ClCOCCBr
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Agent: [K]
Product: O=[N+]([O-])C(COCCBr)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
2,2,2-trinitroethyl 2-nitroxyethyl ether (TNEN) is prepared by the reaction of potassium nitroform with chloromethyl 2 2-bromoethyl ether to form 2,2,2-trinitroethyl 2-bromoethyl ether which is then reacted with silver nitrate to form the desired product TNEN as shown in the following reaction scheme: ##STR1## Example 1 shows a method of preparing the starting material chloromethyl 2-bromoethyl ether. Example 2 illustrates suitable conditions for reacting potassium nitroform with chloromethyl 2-bromoethyl ether to produce the intermediate product 2,2,2-trinitroethyl 2-bromoethyl ether. Finally, example 3 illustrates suitable conditions for reacting the 2,2,2-trinitroethyl 2-bromoethyl ether with silver nitrate to produce the final product 2,2,2-trinitroethyl 2-nitroxyethyl ether.
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[SH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15]>C(Cl)Cl>[CH:5]1([NH:10][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:12]=2[SH:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1ccc(OC)cc1S
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CCCC2)c(S)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
AlMe3 (10 mmol, 2.0 M in toluene) was added dropwise to a cooled (0° C.) suspension of cyclopentylamine (0.85 g, 10 mmol) in CH2Cl2 (30 mL). When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 30 minutes until the gas evolution ceased. Then, a solution of methyl 2-mercapto-4-methoxy-benzoate (0.990 g, 5 mmol) was added. After stirring at 60° C. for 12 h, the mixture was cooled, and carefully quenched with 5% aq HCl (20 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with a saturated aqueous solution of NaHCO3 (15 mL) and brine. The organic phase was dried using MgSO4 and evaporated, filtered and the solvent was evaporated in vacuo. The resulting residue was purified by crystallization from Et2O to afford N-cyclopentyl-2-mercapto-4-methoxybenzamide as a tan solid (1.18 g, 94%). 1H NMR (DMSO-d6, 300 MHz): δ 8.26 (s, 1H), 7.51 (d, 1H, J=8.7 Hz), 7.01 (s, 1H), 6.72 (d, 1H, J=8. Hz), 5.62 (s, 1H), 4.16-4.14 (m, 1H), 3.78 (s, 3H), 1.99-1.80 (m, 2H), 1.79-1.68 (m, 2H), 1.66-1.53 (m, 4H). LC-MS (ESI) Calcd for C13H17NO2S [M+H]+: 252.09. Found: 251.95.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][C:1](=[O:3])[CH3:2])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)Oc1ccccc1C(=O)NC(C)(C)C

Procedure:
Following the procedure of Example 1 above and using 2-acetoxybenzoyl chloride and tert-butylamine, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](=O)(OC)[O:12]C.C[O-].[Na+]>CO>[Br:10][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:11](=[O:12])[O:9][CH2:8][C:7]=2[CH:6]=1
Reactant: Nc1ncc(Br)cc1CO
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a stirred solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (3.0 g, 15 mmole) in methanol (30 mL) was added dimethyl carbonate (5 mL, 60 mmole) and sodium methoxide (25 wt % solution in methanol, 4 mL, 17.4 mmole). The reaction was heated at reflux for 18 hr, cooled to RT, and concentrated to dryness. The remaining residue was triturated with saturated aqueous NH4Cl (50 mL), filtered, washed with cold H2O (50 mL), and dried under vacuum to give the title compound (1.75 g, 51%) as a beige solid: LCMS (ES) m/e 229.0 (M+H)+; 1H NMR(400 MHz, DMSO-d6) δ 10.90 (s,1H), 8.31 (s,1H), 7.90 (s,1H), 5.31 (s, 2H).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.N>C(O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(N)=S
Agent: N
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 70 °C
Yield: 89.9 %

Procedure:
Thioacetamide (1.73 g, 23.03 mmol) was added to a solution of 2-bromo-1-(4-fluorophenyl)ethanone (5.0 g, 23.03 mmol) in ethanol (50 mL) and the reaction was refluxed at 70° C. for 4 h. The reaction mixture was then cooled to room temperature, neutralized to pH 7 with aqueous ammonia solution (20 ml), and extracted with ethyl acetate (200 mL). The combined extracts were washed with water (100 mL), dried over Na2SO4, and concentrated to provide 4-(4-fluorophenyl)-2-methylthiazole (4.0 g, 90%). 1H NMR (400 MHz, DMSO) δ 7.95-8.00 (m, 2H), 7.91 (s, 1H), 7.23-7.29 (m, 2H), 2.71 (s, 3H). MS (ESI) m/z: Calculated for C10H8FNS: 193.04. found: 194.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:29]=[CH:28][C:12]3[C:13]([CH3:27])([CH3:26])[CH2:14][CH:15]([NH:19]C(=O)C(F)(F)F)[C:16](=[O:18])[NH:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[OH-].C1COCC1.[OH-].[Na+]>CO>[NH2:19][CH:15]1[CH2:14][C:13]([CH3:26])([CH3:27])[C:12]2[CH:28]=[CH:29][C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:30][C:31]4[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=4[C:33]([NH:35][CH3:36])=[O:34])[C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:10][C:11]=2[NH:17][C:16]1=[O:18]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(N)CC3(C)C)ncc1Cl
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Combined 2-{5-Chloro-2-[5,5-dimethyl-2-oxo-3-(2,2,2-trifluoro-acetylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (355 mg, 0.000598 mol), 1 M of NH4OH in Methanol (2 mL), and THF (50 mL, 0.6 mol;). Added 2 mL of 50% NaOH and stirred for 2 hr. Product isolated as a white solid (244 mg, 82%). LCMS 498.22 (M+H), HPLC purity 94%, 1H-NMR (CDCl3, 400 MHz) δ 8.90 (bs, 1H), 8.05 (s, 1H), 7.93 (bs, 1H), 7.63 (bs, 1H), 7.44-7.39 (m, 2H), 7.35-7.31 (m, 2H), 7.28-7.26 (m, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.71 (bs, 1H), 3.40-3.37 (m, 1H), 2.93 (d, J=4.7 Hz, 3H), 2.31-2.27 (m, 1H), 1.99-1.96 (m, 2H), 1.88-1.85 (m, 1H), 1.38 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:29](=[N:30][OH:31])[C:28](=[O:32])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].[N+](=[CH2:35])=[N-]>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:29](=[N:30][O:31][CH3:35])[C:28](=[O:32])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(=NO)[C@H]2SC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CON=C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In ether (6 ml) is dissolved diphenylmethyl 3-acetoxymethyl-7-hydroxyimino-3-cephem-4-carboxylate (349 mg), and under ice-cooling, an ethereal solution of diazomethane (1 ml, 0.77 mmol) is added. While the temperature raised gradually to room temperature, the mixture is stirred for an hour. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin-layer chromatography (developer: ethyl acetate-hexane=1:1) to give diphenylmethyl 3-acetoxymethyl-7-methoxyimino-3-cephem-4-carboxylate (75 mg).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH2:17])[CH3:16])[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH:17][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:16])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCC1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of (S)-1-(1-cyclobutyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (251 mg, 1.1 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (260 mg, 1.1 mmol) and DIPEA (1.0 mL, 5.5 mmol) in n-butanol (4 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 373 as a white solid (140 mg, 36%). LCMS (Method K): RT 2.93 min [M+H]+ 352.1 1H NMR (DMSO-d6, 400 MHz): δ 12.97 (1H, br), 8.33-7.76 (3H, m), 7.69-7.53 (2H, m), 7.09-6.98 (1H, m), 5.87 (1H, br s), 5.27-5.14 (1H, m), 2.93-2.72 (2H, m), 2.44 (1H, br s), 2.23 (1H, br s), 2.02-1.89 (1H, m), 1.82-1.61 (4H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31]Cl)=[CH:25][CH:24]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:46]4[CH2:47][CH2:48][N:43]([C:41]([CH:37]5[CH2:38][CH2:39][CH2:40][O:36]5)=[O:42])[CH2:44][CH2:45]4)=[CH:25][CH:24]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNCc1ccc(-c2cnc(Cc3ccc(OCCCl)cc3)nc2)cc1
Reactant: O=C(C1CCCO1)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCc1ccc(-c2cnc(Cc3ccc(OCCN4CCN(C(=O)C5CCCO5)CC4)cc3)nc2)cc1
Temperature: 90 °C
Yield: 51 %

Procedure:
{4-[2-(4-{{2-[4-(Tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino]-acetic acid tert-butyl ester can be synthesized by the following procedure. To a solution of (4-{2-[4-(2-chloro-ethoxy)-benzyl]-pyrimidin-5-yl}-benzylamino)-acetic acid tert-butyl ester (0.032 mmol) (from Example 5y) in anhydrous DMF is added sodium iodide (0.0384 mmol) and 1-(tetrahydro-2-furoyl)-piperazine (0.16 mmol). The reaction mixture is heated at 90° C. for 8 h. Purification by preparative LCMS (ACN gradient 10-90%) affords {4-[2-(4-{2-[4-(tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino}-acetic acid tert-butyl ester (51%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 4.3 (m, 4H), 3.85 (m, 4H), 3.76 (m, 3H), 3.52 (m, 4H), 2.35 (m, 4H), 2.0 (m, 4H), 1.48 (s, 9H). MS (m/z) (M+1)+ 617.2.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCCCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Reaction time: 5.5 h
Yield: 11.3 %

Procedure:
In a 200 ml autoclave were placed 5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of piperidine and 45 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. After 5.5 hours, the temperature was lowered to room temperature and disappearance of the starting materials was confirmed by thin layer chromatography followed by removing hexamethylphosphoric triamide using a vacuum pump (120° C./2 mm Hg). To the residue was added several drops of concentrated hydrochloric acid and then ethyl acetate. Crystals which formed were collected by filtration and washed with ethyl acetate. The crystals thus obtained were recrystallized from dimethylformamide-water and the resulting crystals were added sodium hydroxide and water so as to obtain an aqueous solution of pH 13 which then was treated with activated carbon and filtered. The filtrate was adjusted to pH 7 with acetic acid to precipitate crystals which then were collected by filtration and recrystallized from dimethylformamide-water to give 570 mg of 9-fluoro-8-(1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 258°-261° C., white rhombic crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].N/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23]>C(O)CCC>[C:22]([CH2:21][C:20](=[N:13][NH:12][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12)[CH3:24])#[N:23]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: C/C(N)=C/C#N
Solvent: CCCCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NN=C(C)CC#N
Reaction time: 24 h

Procedure:
249 g of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester (1 mol) and 82 g of 3-aminocrotononitrile (1 mol) are heated together in 1.5 liters of butyl alcohol with stirring for 24 hours. The solvent is removed in vacuo and the residual 4-[2-(2-cyano-1-methylethylidene)hydrazino]-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester is recrystallized from alcohol, yield 309 g (80%); m.p. 190°-191°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4].[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O1CCOCC1>[C:17]([O:16][C:14]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][NH:7][CH:8]=1)=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1n[nH]cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
To a mixture of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (50.0 g, 355 mmol) in dioxane (500 mL) was added 2M aqueous NaOH solution (213 mL, 426 mmol), the mixture heated to 50° C. and stirred for 5 h. To this mixture was then added (BOC)2O (81.4 g, 373 mmol), using a dioxane rinse (100 mL) and the mixture heated at 50° C. for a further 5 h, then stirred at ambient for 14 h. The dioxane was removed in vacuo and water (1 L) added. The mixture was taken to pH 2 using conc. aqueous HCl solution and the solid formed collected by filtration and dried on the filter. The solid was dried further through azeotrope with toluene (x3) and in the vacuum oven to give 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (70.0 g, 87%) as a violet solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NC1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCOCC3)n2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.277 g, 0.73 mmol) in N-methylpyrrolidone (1.25 ml) was added tetrahydro-2H-pyran-4-amine (0.147 g, 2 eq.), the mixture was stirred for 1 hour and then water (1.25 ml) was added dropwise. This resulted in a precipitate being formed, which was collected by filtration, and dried in vacuo (0.258 g). This material was then purified by autopurification to give the title compound as a colourless solid (0.116 g, 40%).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC[C@@H]1CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC[C@H]1CO
Reaction time: 14 h
Yield: 69.1 %

Procedure:
Said solution of (S)-azetidine-2-methanol was adjusted to pH 10 by adding 10% sulfuric acid, sodium hydrogen carbonate (2.00 g, 24.0 mmol) was then added and benzyloxycarbonyl chloride (ZCl) (4.00 g, 24.0mmol) was added at room temperature. Thereafter, stirring was continued for 14 hours. The mixture was adjusted to pH 7 and extracted with ethyl acetate (50 mL ×1), the extract was washed with water (50 mL×1) and dried over magnesium sulfate and, after filtering off the same, the filtrate was concentrated. This was subjected to column chromatography (Wakogel C-200) using toluene/ethyl acetate (1/1) as a mobile phase for separation and purification, whereby a pale yellow oil was obtained (1.50 g). Based on its proton NMR spectrum (FIG. 3), this was identified as the desired product (S)-N-benzyloxycarbonylazetidine-2-methanol (yield 69.1%). Further, as a byproduct, there was obtained (S)-2-N-benzyloxycarbonyl-1,4-butanediol (0.27 g, yield 11.4%). Its proton NMR spectrum is shown in FIG. 4.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:27]2[CH2:26][CH2:25][N:24]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:23]([CH3:22])[CH2:28]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2C(C)(C)C)cc1

Procedure:
136 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 2-methyl-1-m-tolylpiperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: C([N:8]([CH2:23][CH:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])[C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([NH:8][CH2:23][CH:24]([OH:34])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])([CH3:21])[CH3:22])=[N:13][CH:14]=1)(=[O:20])[NH2:19]
Reactant: [H][H]
Reactant: Cc1ccccc1OCC(O)CN(Cc1ccccc1)C(C)(C)COc1ccc(C(N)=O)cn1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1OCC(O)CNC(C)(C)COc1ccc(C(N)=O)cn1

Procedure:
A solution of 22 g of crude 1-[N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethyl]-amino]-3-(2-methyl-phenoxy)-2-propanol in 220 ml of methanol is hydrogenated analogously to Example 1, a total of 6 g of palladium-on-charcoal catalyst (5% strength) being added in 2 portions in order that the calculated amount of hydrogen should be taken up. Working up gives an oil from which 1-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethylamino]-3-(2-methyl-phenoxy)-2-propanol of melting point 122°-128° C. is obtained by crystallisation from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: CC1(N)COC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 28 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 3-methyl-oxetan-3-yl-amine instead of 2-hydroxy-2-methylpropylamine, to the title compound (17 mg, 28%) which was obtained as a white solid. MS: m/e=400.3 [M+H]+.
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17].Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17]
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCCCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To DMF (40 mL) was added potassium carbonate (9.1 g, 65.9 mmol) and methyl 3-hydroxy-4-methoxybenzoate (10.0 g, 54.9 mmol) and the mixture stirred 30 minutes at room temperature 1-bromo-2-chloroethane (11.0 g, 76.8 mmol) was added and the mixture was heated at 60° C. overnight at which point excess 1-bromo-2-chloroethane (5.5 g, 38.4 mmol) was added and heating continued for 8 hours. After cooling to room temperature, the mixture was diluted with H2O, filtered, and the solid washed with EtOAc to give methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.04 g, 16.6 mmol, 30%). 1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, 1H), 7.47 (s, 1H), 7.11 (d, 1H), 4.29 (t, 2H), 3.95 (t, 2H), 3.86 (s, 3H), 3.81 (s, 3H); LC-MS (ESI) m/z 245 (M+H)+.