Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[CH2:12][CH:11]2[NH:13][CH:7]([CH2:8][O:9][CH2:10]2)[CH2:6]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:13]1[CH:7]2[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH2:12][CH:11]1[CH2:10][O:9][CH2:8]2)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CC1CC2COCC(C1)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AG) (179 mg, 0.90 mmol) in 10 mL of dichloromethane was added triethylamine (0.5 mL, 3.6 mmol). The mixture was stirred at room temperature for 15 mins and then benzyl chloroformate (0.25 mL, 1.8 mmol) was added dropwise at 0° C. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated in vacuo. The residue was purified by flash column chromatography to afford 7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester as colorless oil (Compound AI) (0.13 g, 44%) MS: calc'd (MH+) 334, measured (MH+) 334.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:15]1COCC1.C[Li].Cl>CCOC(C)=O>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: Cl
Agent: [Li]C
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (10.0 g, 48.5 mmol) and THF (100 mL) was cooled to <5° C. and methyllithium (95 mL, 1.6M solution in diethyl ether, 152 mmol) was slowly added, keeping the internal temperature <20° C. The resulting solution was warmed to ambient temperature and stirred for 1 hour. The solution was then cooled to 10° C. and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (10.3 g). This material was used without further purification in the next step.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:28][C:27]([F:30])([F:29])[O:26][C:22]1[CH:21]=[C:20]([C:2]2[N:35]=[C:5]([CH:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(OC(F)(F)F)c2)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Add tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)-piperidine-1-carboxylate (1.50 g, 3.48 mmol) to a mixture of ammonium acetate (1.40 g, 18.1 mmol), and glacial acetic acid (10 mL) and heat at reflux for 15 h. Cool the mixture to room temperature and concentrated in vacuo. Dissolve the residue in ethyl acetate (50 mL) and adjust to pH 8 with saturated NaHCO3. Extract the aqueous layer with ethyl acetate (2×50 mL). Combine the organic layers, dry (Na2SO4), filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (80 g, eluting with a gradient of 10% to 20% methanol/ethyl acetate, 1.5 L) to provide 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (491 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:15][CH3:16].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.C(=O)([O-])[O-]>COCCO>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: COc1c(N)ccc2c1CCCC(=O)N2C
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3C)ncc1Cl
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a solution of 7-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50 mg, 0.227 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (56 mg, 0.189 mmol) in 2.27 mL of 2-methoxyethanol was added 57 μL of 4M HCl in Dioxane (0.227 mmol). The solution was heated to 110° C. for 5 hrs, followed by the addition of MP-Carbonate (135 mg, 0.43 mmol) at RT. The MP-Carbonate was filtered after 30 minutes and the resulting crude material was chromatographed (ISCO) to give 2-[5-Chloro-2-(6-methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23 mg, 25%). 1H-NMR (CDCl3) δ 11.12 (s, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.51 (t, J=7.7 Hz, 2H), 7.43 (s, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.90 (t, J=8.8 Hz, 1H), 6.26 (br s, 1H), 3.80 (s, 3H), 3.33 (s, 3H), 3.04 (s, 3H), 2.0-2.4 (m, 6H); LC/MS (ESI-pos) m/z 481.06 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]#[N:30]>O1CCCC1>[C:29]([CH2:28][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:30]
Reactant: N#CCBr
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Example 266A (5.25 g, 23.0 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (23.00 mL, 23.0 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (1.56 mL, 23.0 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 289 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>O1CCCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][NH:33][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:39]
Reactant: CCOC(=O)CN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 50.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The ethyl glycinate (2.65 g, 0.019 mole) and triethylamine (1.92 g, 0.019 mole) were added dropwise and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([Cl:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([Cl:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccncc1
Reactant: CCOC(=O)c1cc(Cl)sc1N
Product: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-5-chloro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:28]=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:14]=1)=[O:11].O>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[CH:28][C:19]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cncn1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
To a solution of 1,2,4-triazole (18 mg, 0.258 mmol) in DMF (1 mL), NaH (11.5 mg 60% in mineral oil, 0.282 mmol) was added and the slurry was stirred at room temperature for 5 min. To the slurry, 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (70 mg, 0.235 mmol) in DMF (2 mL) was added at room temperature at stirred for 2 days. Water (5 mL) was added and the reaction mixture was extracted with ethyl acetate (25 mL). The organic phase was dried over MgSO4, the solvent evaporate in vacuo, and the resulting solid was purified by preparative LCMS to afford N-[3-(quinoxalin-2-yl)phenyl]-2-(1H-1,2,4-triazol-1-yl)acetamide (56 mg, 72% yield). LCMS calculated for C18H14N6O (M+H): 331.34. found 331.11. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.65 (1H, br. s), 9.52 (1H, s), 8.58 (1H, s), 8.55 (1H, m), 8.12 (1H, m), 8.10 (1H, d, J=7 Hz), 8.04 (1H, s), 7.98-7.80 (3H, m), 7.58 (1H, m), 5.21 (2H, s).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:29]=[CH:30][C:23]=23)=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C.O>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:34]2[CH2:33][CH2:32][CH:31]([N:28]3[C:24]4=[N:25][CH:26]=[N:27][C:22]([O:21][C:20]5[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[C:23]4[CH:30]=[N:29]3)[CH2:36][CH2:35]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
4-Nitrophenyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 268 mg, 1.33 mmol) was added in three portions to a cooled (˜0° C.) solution of 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 28; 275 mg, 0.89 mmol), and diisopropylethylamine (390 μL, 2.2 mmol) in anhydrous dichloromethane (10 mL). The mixture was warmed to room temperature and stirred for 1 h. Water (10 mL) was added, the layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a 23 g Supelco column, eluting with 0-7% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (180 mg, 43%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 79.8 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.73 g of 5-[4-{2(S)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 37), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid were used, to give 0.39 g of the title compound having a melting point of 55° C. to 60° C. (softening) and having [α]D =-52.4° (methanol, c=0.990).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:29])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:17](=[O:19])[CH3:18])(C)(C)C>>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:29]
Reactant: CC(=O)C(Cc1ccc(F)cc1F)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(F)cc1F)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2,4-difluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10]CC)=[O:9].B(F)(F)F.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][O:29]/[C:30](=N/[H])/[C:31](Cl)(Cl)Cl)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>C1(C)C=CC=CC=1>[CH2:4]([C@@:3]1([C:8]([OH:10])=[O:9])[CH2:2][CH2:7][CH2:6][CH2:31][C@H:30]1[O:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1O
Reactant: [H]/N=C(/OCCc1ccc(OC)c(OC)c1)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC[C@@]1(C(=O)O)CCCC[C@H]1OCCc1ccc(OC)c(OC)c1
Yield: 110.3 %

Procedure:
To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH:20]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21].Br[CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36].Cl>C1COCC1.O>[CH:20]([O:23][C:24]([C:26]1([CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21]
Reactant: CCC(CC)CBr
Reactant: CC(C)OC(=O)C1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a solution of dicyclohexylamine (4.263 g, 23.5 mmol) in THF (10 mL) 1.6 M n-BuLi in hexane (13.23 mL, 21.15 mmol) was added with stirring over 20 min at temperature between −20° C. and −15° C. This orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this orange suspension a solution of cyclohexanecarboxylic acid isopropyl ester (3.0 g, 17.63 mmol) in THF (22 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (4.073 g, 24.7 mmol) in THF (11 mL) was added at the same temperature over 15 min. Stirring at 0° C. was continued overnight and for an additional 2 h at room temperature. At 5° C. cold water (20 mL) was added, followed by 2N HCl (50 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (4.7 g) was distilled at 50° C. (0.01 mbar) to give 3.95 g (88%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester as colorless oil, purity 97% (GC area).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
The compound (820 mg, 2.6 mmol) prepared in Example 1 was dissolved in dichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol) and triethylamine (0.81 ml, 3.1 mmol) were added thereto, and the mixture was stirred for 30 min at 0° C. After completion of the reaction, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (600 mg, Yield 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][CH2:13][CH2:14]O)=[N:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].S(Cl)([Cl:19])=O>CN(C)C=O>[ClH:19].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][N:9]3[C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2sc(NCCO)nc2c1
Solvent: CN(C)C=O
Product: Cl
Product: O=[N+]([O-])c1ccc2c(c1)N1CCN=C1S2
Reaction time: 4 h
Yield: 85 %

Procedure:
To a stirred and cooled (0° C.) solution of 19 parts of 2-[(5-nitro-2-benzothiazolyl)amino]ethanol in 18 parts of N,N-dimethylformamide is added dropwise (slowly) a solution of 10.7 parts of thionyl chloride in 207 parts of N,N-dimethylformamide. Upon completion, the mixture is stirred and heated slowly to reflux and stirring at reflux is continued for 4 hours. After cooling, the precipitated product is filtered off and washed with N,N-dimethylformamide and 2,2'-oxybispropane, yielding 17.5 parts (85%) of 2,3-dihydro-6-nitroimidazo[2,1-b]benzothiazole monohydrochloride; mp. 314°-316° C. (dec.).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:12]=1)[NH2:2].[C:17](/[N:19]=[C:20](\OC1C=CC=CC=1)/[NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[C:24]([F:39])[CH:23]=1)#[N:18]>C(O)(C)C>[N:5]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:12]=[C:3]([N:1]2[C:17]([NH2:18])=[N:19][C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH:31]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:30][CH2:29]4)=[C:24]([F:39])[CH:23]=3)=[N:2]2)[N:4]=1
Reactant: NNc1cc2c(nn1)-c1ccccc1CC2
Reactant: N#C/N=C(/Nc1ccc(N2CCC(N3CCCC3)CC2)c(F)c1)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCC(N4CCCC4)CC3)c(F)c2)nn1-c1cc2c(nn1)-c1ccccc1CC2

Procedure:
3-Hydrazinyl-5,6-dihydrobenzo[h]cinnoline (51 mg, 0.24 mMol) and (Z)-phenyl N′-cyano-N-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)carbamimidate (98 mg, 0.24 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The crude product was purified by radial chromatography on silica gel, eluting with 95% dichloromethane and 5% 2M ammonia in methanol to give 1-(5,6-dihydrobenzo[h]cinnolin-3-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #170; 1H NMR (CDCl3/MeOD4, 300 MHz) 10.84 (s, 1H), 8.43 (d, 1H), 7.75 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2H), 7.26 (m, 2H), 6.93 (t, 1H), 3.42 (m, 2H), 3.00 (m, 3H), 2.60-2.75 (m, 6H), 2.15 (m, 1H), 1.98 (m, 2H), 1.74-1.95 (m, 7H) ppm; MS (ES) 526.43 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>CCO.[Pd]>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[N:3][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1F
Yield: 78.5 %

Procedure:
2-Fluoro-3-methyl-5-nitropyridine (8.2 g, mmol) was combined with 5% Pd/C (100 mg) in EtOH (100 mL) under a H2 atmosphere for 16 hours. The mixture was filtered and concentrated, and the crude product was chromatographed (silica gel; CHCl3 /MeOH 99:1 to 96:4) to afford a solid (5.2 g, 78% ): 1H NMR (DMSO-d6, 300 MHz) δ2.10 (s, 3H), 5.11 (brs, 2H), 6.95 (dd, J=8.14 Hz, 1H), 7.26 (t, J=2.72 Hz, 1H); MS (CI/NH3) m/z: 127 (M+H)+, 144 (M+NH4)+.
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:12]2[CH2:13][C:14](=O)[C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5].O.NN>O1CCOCC1>[C:4]([C:7]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5]
Reactant: COc1ccc2c(c1)C(=O)Cc1c(cccc1C(=O)O)S2
Agent: NN
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2

Procedure:
To the mixed solvent of 16ml of ethanol and 16ml of dioxane were added 1.8g of 9-carboxy-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 2.0g of hydrazine hydrate and the resulting mixture was heated under reflux for 8 hours. After the completion of reaction, the solvent was distilled off and 1.8g of sodium hydroxide and 30ml of diethylene glycol was added to the residue. The thus obtained mixture was heated under reflux at 190°-200° C for 5 hours. After cooling, water was added to the mixture which was extracted benzene. The aqueous layer was acidified with hydrochloric acid and extracted with benzene. The extract was washed with water, dried and the solvent was distilled off. The thus obtained residue was chromatographed over silica gel, eluted with chloroform-diethylether (10:1), there was obtained 0.5G of 9-carboxy-2-methoxy-10,11-dihydrodibenzo[b,f]thiepin as colorless needles having a melting point of 185°-187° C.
Reaction SMILES: CO.[Cl:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>>[Cl-:3].[CH2:13]([N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH3:14]
Reactant: OCCOCCOCCCl
Reactant: CCN(CC)CC
Solvent: CO
Product: CC[N+](CC)(CC)CCOCCOCCO
Product: [Cl-]
Temperature: 130 °C
Yield: 95 %

Procedure:
An autoclave (capacity: 500 ml) was charged with 200 parts of methanol and 94.5 parts of triethylamine. After heating the mixture to 130° C., 135 parts of 2-[2-(2-chloro-ethoxy)ethoxy]ethanol was added over a period of 1 hour and the resulting mixture was heated at 130° C. for an additional 4 hours. Crystallization was performed as in Preparation 1 to obtain 205.0 parts of triethyl 2-[2-(2-hydroxy-ethoxy)ethoxy]ethylammonium chloride (yield: 95%).