Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54]O)[O:34][C@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[O:34][C@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of dry pyridine (0.456 mL) in methylene chloride (20 mL) cooled to -15° C. was added trifluoromethanesulfonic anhydride (0.864 mL). The mixture was stirred during 15 min at -10° C., then methyl 2,3,4-tri-O-benzyl-β-D-glucopyranoside (1.2 g, 2.58 mmol) in methylene chloride (30 mL) was added [P. Kovac, J. Alfoldi and M. Kosik, Chem. Zvesti 28, 820, (1974)]. The mixture was stirred during 1.5 h at -10° C. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:2 mixture of hexane and ethyl acetate afforded the expected compound methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl -β-D-glucopyranoside (1.408 g, 89%) as an oil, which crystallized in the fridge.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22]C2C=CN=CC=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:4][CH2:3]1.C([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=O>>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH2:22][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](N(Cc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=Cc1cccnc1
Product: C[C@H]1CC[C@H](N(Cc2cccnc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-Methyl-cyclohexyl)-3-pyridin-4-ylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-formyl-pyridine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.[CH2:38]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][N:39]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(C(C)C)CC)(C)C>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:46]4[CH2:45][CH2:44][C:43]5([CH2:38][N:39]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:40][CH2:41][CH2:42]5)[CH2:48][CH2:47]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 0.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, 0.337 g (1.15 mmol) of tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate hydrochloride (1:1) (CAS 1023301-88-3) and 0.224 g (1.7 mmol) of diisopropylethylamine in 2 ml of pentanol is heated under reflux for 40 hours at 140° C. The solvent is then evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 100/0/0 to 90/10/1) in order to give 0.190 mg of tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in methanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:16]1[CH2:17][CH2:18][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:79]5[CH2:80][CH2:81][CH:76]([N:71]6[CH2:75][CH2:74][CH2:73][CH2:72]6)[CH2:77][CH2:78]5)=[O:33])=[CH:35][CH:36]=4)=[O:37])=[CH:21][CH:20]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 58.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (37 mg, 58% yield); MS (ESI) m/z=642.7
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:18]([O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a solution of 10.00 g (45.2 mmol) of methyl 3,5-dichloro-4-hydroxybenzoate dissolved in 100 mL of CH2Cl2 was added 11.06 g (90.2 mmol) of 4-dimethylaminopyridine and 8.18 g (54.2 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HC1, saturated NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 7.70 g (51%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[N:12])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:16]1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.CO>[CH3:16][O:14][C:13](=[O:15])[C@@H:9]([CH2:10][C:11]#[N:12])[NH:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: CCCCOC(=O)N[C@H](CC#N)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)N[C@H](CC#N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of N-butyloxycarbonyl-3-cyano-D-alanine (20.5 g, 97 mmol) and 4-dimethylaminopyridine (11.85 g, 97 mmol) in 150 mL THF and 33 mL methanol was added N,N'-dicyclohexylcarbodiimide (20 g, 97 mmol) and the solution was allowed to stir at room temperature for 2 hours. Insoluble material was removed by filtration and the solution was concentrated. The residue was taken up in ethyl acetate and the solution was washed with 5% citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Crystallization from ethyl acetate gave 18.8 g (85%) product. 1H-NMR: d (CDCl3) 5.48 (d, 1H); 4.54 (m, 1H); 3.84 (s, 3H); 2.98 (m, 2H); 1.44 (s, 9H). ES-MS: calcd M+1 229.2; found 229.0.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][O:11][C:8](=[O:20])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC(=O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCOC(=O)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
50 g of 4-acetoxycyclohexanone, dissolved in 150 ml of chloroform, were treated at 40° C. in the course of 40 minutes, with stirring, with 136 g of m-chloroperbenzoic acid (55% strength), dissolved in 500 ml of chloroform. The reaction mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the precipitated solid (m-chlorobenzoic acid), was filtered off with suction. The chloroform phase was extracted twice by shaking with 20% strength aqueous sodium carbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. 46.4 g of 4-acetoxycaprolactone (84%, based on the 4-acetoxycyclohexanone employed) were recovered from the residue obtained in this way by bulb tube distillation.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N)o1
Reaction time: 18 h
Yield: 52.2 %

Procedure:
A mixture of methyl 5-nitro-2-furoate (13 g, 76 mmol) and 10% Pd/C (1.3 g) in ethanol (150 mL) was shaken under an atmosphere of hydrogen at 40 psi for 18 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) provided methyl 5-amino-2-furoate (5.6 g): 1H NMR (500 MHz, CDCl3) δ 7.11-7.10 (m, 1H), 5.31-5.29 (m, 1H), 4.31 (br s, 2H), 3.84 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][O:21][CH2:22]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][NH:8][CH2:16]2)=[CH:11][C:12]=1[N:18]1[CH:19]2[CH2:25][CH2:24][CH:23]1[CH2:22][O:21][CH2:20]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C4CCC3COC4)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1N1C3CCC1COC3)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 267.1 ([{37Cl}M+H]+, 43%), 265.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(C)CBr

Procedure:
To ethyl 3-methyl-2-butenoate (10.0 g, 78.0 mmol) in 80 ml of carbon tetrachloride heated under gentle reflux is added N-bromosuccinimide (15.0 g, 84.0 mmol) in portions, followed by traces of radical initiator (benzoyl peroxide, ca. 0.2 g, and AIBN, ca. 0.1 g) in portions over one hour. After the final addition, the mixture is heated under reflux for 30 min. The reaction mixture is cooled and filtered and the solvent is removed by rotoevaporation to give ethyl 4-bromo-3-methyl-2-butenoate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH2:9]1)=O)(C)(C)C.O.[OH-].[Na+]>C1COCC1>[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN2CCN(Cc3ccccc3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@@H](CN2CCN(Cc3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g of the compound obtained in step 3.2 dissolved in 45 ml of THF are added to a solution of 1 g of LiA1H4 in 45 ml of THF cooled to 0° C. The medium is stirred at AT for two hours and then cooled to 0° C. 0.96 ml of water and then 3 ml of 5M NaOH are added, the medium is then filtered, and the solid is rinsed with ether. The filtrate is evaporated, taken up in ether, and washed twice with a saturated NaHCO3 solution and then with a saturated NaCl solution. After drying over MgSO4 and evaporation, 3.5 g of the desired compound are recovered.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]4)=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1cc(CC)n(-c2cccc3nc(Nc4c(C)cc(Br)cc4OC)n(C)c23)n1
Temperature: 110 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of 83 mg (0.287 mmol) of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole, 186 mg (0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 20 hours. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to give 112 mg (83%) of the title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[N:21]([C:22]3[S:23][C:24]4[C:25]([N:34]=3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:9]=1>CO>[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:17][NH:18][CH2:19][CH2:20][N:21]2[C:22]2[S:23][C:24]3[C:25]([N:34]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ncc(C(F)(F)F)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc2nc(N3CCNCC3COc3cccnc3)sc2c1
Reaction time: 8 h
Yield: 52 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 3-((pyridin-3-yloxy)methyl)-4-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (134 mg, 0.271 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were combined and brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.036 mL) was added. The mixture was concentrated under reduced pressure to give 60.5 mg (52%) of the desired product as the hydrochloride salt. LC-MS: RT=4.53 min, [M+H]+=396.6.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]3[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]3[CH2:13]2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(N2Cc3nc(C(=O)O)nn3-c3cccnc32)cc1

Procedure:
using 10.00 g (0.037 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 15.80 g (0.128 mol) of 4-methoxyaniline there is obtained 5-(4-methoxyphenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/isopropanol, melts at 190°-196°;
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]=O>C(O)(=O)C>[ClH:8].[C:2]([NH:6][N:7]=[CH:11][C:10]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:9]=1[Cl:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=Cc1c(F)cccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)NN=Cc1c(F)cccc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of t-butyl hydrazine hydrochloride (1.24 g, 10 mmol) and 2-chloro-6-fluorobenzaldehyde (1.1 mL, 10 mmol) dissolved in acetic acid (5 mL) was stirred at 50° C. for half hour. Hexanes (10 mL) was added, filtered and washed the white solid with hexanes (20 mL). Yield: 61%. ESMS: 229 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:37])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (460 mg, 1.0 mol) (from Example 12b, Step 6 above) in CH2Cl2 was treated with a solution of 37% aq formaldehyde (1 ml) and NaBH(OAc)3 (436 mg, 2.0 mol) and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 330 mg (70%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate. MS found: (M+H)+=460.49.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:14]([N:18]1[C:26]2[N:25]=[C:24]([Cl:27])[NH:23][C:22]=2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH2:31]/[C:32](=[N:35]/[H])/[NH:33]O)[C:19]1=[O:37])[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:14]([N:18]1[C:26]2[N:25]=[C:24]([Cl:27])[NH:23][C:22]=2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH2:31][C:32]2[N:33]=[C:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[O:12][CH3:13])[O:11][N:35]=2)[C:19]1=[O:37])[CH2:15][CH2:16][CH3:17]
Reactant: COc1c(Cl)cccc1CC(=O)O
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3cccc(Cl)c3OC)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
A mixture of [3-chloro-2-(methyloxy)phenyl]acetic acid (32 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDl (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (25 mg, 28%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: NCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(NCC3CCCCC3)c(C#N)c2)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In 3 ml of DMSO was dissolved 247 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate, and 0.31 ml of aminomethylcyclohexane was added thereto. After being stirred at 40° C. for 17 hours, the reaction solution was diluted with ethyl acetate and washed with water and brine, successively. The organic layer was dried and concentrated under reduced pressure and then recrystallization was performed from a mixed solvent of diisopropyl ether and hexane to obtain 266 mg of methyl 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate. (2) Then, 266 mg of the compound was dissolved in a mixed solvent of 5 ml of methanol and 10 ml of THF, and 1.14 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 80° C. for 1 hour. After cooling, the reaction solution was diluted with water and washed with diethyl ether. The resulting aqueous layer was neutralized with 1M hydrochloric acid and extracted with ethyl acetate and the organic layer was dried and concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethanol and water to obtain 199 mg of 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinic acid. Then, 199 mg of the compound was dissolved in 10 ml of ethanol and 0.59 ml of a 1M aqueous sodium hydroxide solution was added thereto. After stirring at room temperature for 15 minutes, the reaction solution was concentrated. The resulting residue was washed with 2-propanol to obtain 181 mg of sodium 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate.