Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH2:25]=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1.CO>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Solvent: CO
Solvent: CCO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Following the same procedure as described for (−) (18), cinchonidine (8.61 g, 29.3 mmol) in hot ethanol (175 mL) was added to a solution of (±)20 (10.0 g, 29.3 mmol) in hot ethanol. The solution was allowed to cool to room temperature and a portion of the solvent was removed under reduced pressure. Crystals obtained were collected by filtration, 6.6 g, mp 204-205° C. The optical rotation was measured at 21° C.: [α]D−73.3° (c=0.5, methanol). The salt was recrystallized from ethanol to give fluffy white crystals, 3.7 g, mp 206-207° C. The optical rotation was measured at 21° C.: [α]D−74.2° (c=0.5, methanol). The acid was recovered from salt, as described previously for (−)18, to obtain a white solid, 1.7 g. mp 150-15 1° C. The optical rotation was measured at 21° C.: [α]D−28.4° (c=1.2, methanol). Anal:(C20H23NO4); Calculated C 70.36, H 6.79, N 4.10; found C 70.17, H 6.86 and N 4.05
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH:39]1[C:1]([C:3]2[CH:4]=[C:5]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=5[CH:24]=[CH:25][C:10]3=4)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:41]=[N:40]1
Reactant: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2cccc(-c3nnn[nH]3)c2)c2ccc3c(c2N1)CCCC3
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To an anhydrous DMF (5 mL) solution of 5-(3-cyanophenyl)-8,9,10,11-tetrahydronaphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (302 mg, 0.91 mmol) was added tri-n-butyltin azide (499 μL, 1.82 mmol). The mixture was stirred at 110° C. for 24 hours. The reaction mixture was cooled on standing, poured into saturated aqueous sodium hydrogen carbonate solution, and washed with ethyl acetate. After neutralization of the aqueous layer by addition of 1M hydrochloric acid, the layer was extracted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by chromatography (chloroform/methanol=95/5) to give the titled compound as slightly yellow powder (242 mg, yield 71%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14]([NH2:22])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=C[CH:16]=1.Cl.C(Cl)C1C=CC=NC=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:16]([C:15]3[CH:14]=[N:22][CH:18]=[CH:19][CH:20]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: Cl
Agent: ClCc1cccnc1
Product: COc1ccc2c(O)nc(-c3cccnc3)nc2c1C
Yield: 92 %

Procedure:
The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and nicotinyl chloride hydrochloride as acid chloride, which gave the title compound (2.5 g, 92%), [M+H]=268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[N+:11]([C:14]1[C:15]([C:19](Cl)=[O:20])=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].[N+](C1C(C(O)=O)=NNC=1)([O-])=O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:19]([C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:18][NH:17][N:16]=1)=[O:20]
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(Cl)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2n[nH]cc2[N+](=O)[O-])c(N)c1
Reaction time: 8 h

Procedure:
By proceeding in a manner similar to Reference Example 36(a), Method A, above but using 4-methoxy-1,2-phenylenediamine (880 mg) and 4-nitropyrazole-3-carboxylic chloride [prepared by treating a solution of 4-nitropyrazole-3-carboxylic acid (1 g) in dry dichloromethane (70 ml) under nitrogen with oxalyl chloride (1.11 ml) and dimethylformamide and after stirring overnight evaporating the reaction mixture then azeotroping three times with toluene (10 ml)] there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl)-amide (800 mg). LC-MS (Method J): RT=2.67 minutes, 278.25 (M+H)+, 276.28 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17](O)[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17]([F:37])[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1nccc(C(=O)N[C@H]2C[C@H](O)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(C(=O)N[C@H]2C[C@H](F)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluorophenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide (crude, <0.121 mmol) in DCM (5 mL) was added DAST (20.3 μL, 0.154 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (0 to 70% EtOAc in hexanes) to give 2 mg of the title compound, trans-2-methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=5.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.82 (t, J=5.0 Hz, 1H), 7.26-7.21 (m, 1H), 6.54 (tt, J=8.8, 2.2 Hz, 1H), 5.22-5.05 (m, 1H), 4.55-4.43 (m, 1H), 3.79-3.66 (m, 2H), 2.71 (s, 3H), 2.45-2.25 (m, 3H), 2.09-1.92 (m, 3H), 1.74-1.54 (m, 2H). ESI-MS m/z: 419 (M+H)+.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[CH:38]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)([CH3:40])[CH3:39]>CO>[NH2:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([CH:38]([CH3:40])[CH3:39])=[CH:42][CH:43]=2)[CH2:25][CH2:24]1)=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(OC(F)(F)F)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Acetic acid (10 mL) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-isopropylbenzaldehyde (0.060 mmol), NaH3CN (0.15 mmol) and methanol (1.3 mL), and the resulting mixture was stirred at 60° C. for 8 hours, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. A 4 M dioxane solution of HCl (2 mL) was then added to the resulting residue, and the obtained solution was stirred at room temperature overnight, concentrated and then purified by preparative TLC to provide 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compd. No. 1903) (6.6 mg, 26%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 507 (M++H, C26H33F3N4O3).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]=[N:5]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:7]2[N:6]=[N:5][N:4]([CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[OH:13]
Reactant: CC(C)(C)Cn1nnc2cc(O)ccc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (10) (3 mg, 0.015 mmol, 1.0 equiv.) in CHCl3 (500 μL), was added slowly pyridinium tribromide (4.67 mg, 0.015 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature until LCMS showed mostly the desired product. The reaction mixture was quenched with water, neutralized to pH=7, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2). LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(C1C=CC=CC=1)CC>COCCOC>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#Cc1ccccc1
Reactant: [H][H]
Solvent: COCCOC
Solvent: CCCc1ccccc1
Product: CC=Cc1ccccc1
Yield: 46 %

Procedure:
In 1.0 ml of DME were heated 1.0 mmol of 1-phenyl-1-propyne and 0.01 mmol of tetraethylammonium μ-hydride-bis(pentacarbonylchromium(O)) at 100° C. and at a hydrogen pressure of 50 atm for 13 hours with stirring. GLC analysis of the reaction mixture revealed that propylbenzene and β-methylstyrene were produced in a yield of 46% and 10%, respectively.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:20])([F:19])[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
2-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (2.77 g, 8.8 mmol), 4-amino-3-methoxy benzoic acid (1.61 g, 9.6 mmol), i-PrOH (30 mL) and conc. HCl (30 drops) were heated to 95° C. for 18 hours. A this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid (2.74 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=12.13 Hz, 1 H) 1.23-1.42 (m, 2 H) 1.53-1.78 (m, 5 H) 1.82 (d, J=12.63 Hz, 2 H) 3.32 (s, 3 H) 3.94 (s, 3 H) 4.26 (t, J=12.38 Hz, 2 H) 4.52 (t, J=11.62 Hz, 1 H) 7.47-7.65 (m, 2 H) 8.13 (d, J=8.08 Hz, 1 H) 8.28-8.45 (m, 1 H) 9.43 (br. s., 1 H). [M+H] calc'd for C22H25F2N5O4, 462; found 462.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH2:21])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].NC1C(OC)=C2C(C3C=C(C)C=NC=3N2)=C(C2C=C(N[C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])C=CC=2)C=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH:21][C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Reactant: COc1c(N)cc(-c2cccc(NC(=O)C3CC3)c2)c2c1[nH]c1ncc(C)cc12
Product: CCS(=O)(=O)c1cccc(-c2cc(NC(=O)C3CC3)c(OC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 239 by using an analogous procedure to that outlined in the preparation of Compound 241. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (br. s., 4H) 1.16 (t, J=7.33 Hz, 3H) 2.17 (m., 1H) 2.25 (s, 3H) 3.95 (s, 3H) 7.44 (br. s., 1H) 7.78 (br. s., 1H) 7.87 (d, J=7.58 Hz, 1H) 7.96 (d, J=3.28 Hz, 1H) 8.01 (d, J=7.33 Hz, 1H) 8.07 (br. s., 1H) 8.23 (br. s., 1H) 9.88 (br. s., 1H) 12.07 (br. s., 1H); [M+H] calc'd for C25H26N3O4S, 464.2; found, 464.3.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 30.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.9 mg) was obtained.
Reaction SMILES: IC.[CH2:3](N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[CH2:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH:42]2[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:3][N:38]([C:36]([C:33]1[CH:34]=[N:35][C:30]([O:29][CH2:28][C:18]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][C:17]=2[CH3:16])=[CH:31][CH:32]=1)=[O:37])[S:39]([CH:42]1[CH2:44][CH2:43]1)(=[O:40])=[O:41]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NS(=O)(=O)C2CC2)cn1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)S(=O)(=O)C2CC2)cn1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
To a solution of mixture of iodomethane (120 μL, 1.91 mmol), triethylamine (245 μL, 1.75 mmol) and anhydrous sodium carbonate (36.9 mg, 0.35 mmol) in DMF (0.5 mL) was added cyclopropanesulfonic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide (44 mg, 0.11 mmol). The reaction mixture was then heated in the microwave for 40 min at 100° C. The mixture was then cooled and evaporated and the residue was purified by chromatography (SiO2, heptane:ethyl acetate 2:1 to 1:1) to give the title compound (3.9 mg, 9%) as a yellow solid. MS: m/e=486.3 [M+OAc]−.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:15]([F:17])([F:16])[CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[OH:9]
Reactant: O=Cc1ccccc1-n1ccnc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-n1ccnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
To 2-imidazol-1-yl-benzaldehyde (0.344 g, 2 mmol) in THF (8 ml) was added trifluoromethyltrimethyl silane (0.341 g, 2.4 mmol). The reaction mixture was cooled to 0-5° C. (ice water bath) and tetra-n-butyl ammonium fluoride (0.035 ml, 0.035 mmol, 1M in THF) was added. The ice bath was removed, and the mixture was stirred at room temperature for 6 hours. 2N HCl (5 ml) was added, and the reaction mixture was further stirred for 3 hours at room temperature. Solvent was removed on the rotavap under reduced pressure. Crude residue was dissolved in DCM (30 ml), washed with water (20 ml), brine (20 ml) and dried with sodium sulfate. The solvent was removed to give crude 2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethanol (0.45 g, 93%), which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Cl.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33]Br)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:35])[CH2:33][N:15]2[CH2:14][CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1cc(C2=CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C2=CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-Neck round-bottom flask was added 4-(3-Methoxy-4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine; hydrochloride (364 mg, 1.34 mmol) (generated by 4N HCl treatment of the 450 mg of BOC precursor for 1 h), 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (413.0 mg, 1.345 mmol) and cesium carbonate (1095 mg, 3.362 mmol) in acetonitrile (10 mL, 200 mmol). The reaction was stirred overnight at reflux. The reaction mixture was cooled to RT, diluted with water and was extracted (twice) from EtOAc. Combined organic was washed with brine and was dried over MgSO4. After solvent evaporation and flash chromatography (ISCO, EtOAC: MeOH 98:2), the product, 4-{2-[4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester, was isolated as a gum/solid (301 mg, 49%). NMR 1H (DMSO-d6)-7.86 (d, 1H, J=8.54 Hz), 7.29 (s, 1H), 7.17 (d, 1H, J=8.58 Hz), 6.44 (s, 1H), 3.96 (s, 3H), 3.52 (br s, 2H), 3.44 (br s, 2H), 3.32 m with the water peak, 8H), 3.30 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](O)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([Cl:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C

Procedure:
A suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-ol (340 mg, 1.081 mmol) in phosphorus oxychloride (10 mL, 107 mmol) was heated at 100° C. for 24 hours, after which the solvent was removed in vacuo. The resulting oil was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic extract was washed with water (20 mL), dried over MgSO4, filtered, and the solvent removed on a rotary evaporator. This residue was purified using Waters PrepPak and eluting with a gradient of 5-95% ACN/H2O with 0.1% TFA. The desired fractions were combined and the solvent removed in vacuo to give the title compound. LRMS (M+1)=333.8.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: C1CNCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 31.6 %

Procedure:
7-Fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 2.25 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.4 g of piperazine in 30 cm3 of pyridine. After recrystallizing 3 times from, in total, 400 cm3 of dimethylformamide, 0.82 g of 7-fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a deep yellow solid melting at 322-324° C., solvated by 13.6% of dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=2)[C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (Step-1, single enantiomer) and cyclobutanecarbonyl chloride according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:33])[N:2]([CH3:1])[C:3]2[N:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[N:6]=[CH:5][N:4]=2)=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3ncnc(N(C)C(=O)Nc4ccc(F)c(C(F)(F)F)c4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of N-methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (24 mg, 0.077 mmol) in 1.5 ml THF and 2.5 ml toluene, 4-fluoro-3-trifluoromethyl-phenyl-isocyanate (25 μl, 0.17 mmol) is added and the mixture is stirred for 5 h at 100° C. Workup analogously as described in Example 171 gives the title compound: ESI-MS: 519 [MH]+; tR=4.3 min (purity: 100%, gradient J); TLC: Rf=0.43 (DCM/MeOH 9).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:13][N:14]([CH3:16])[NH2:15]>CCO>[CH3:13][N:14]([CH3:16])[N:15]=[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)CCC(=O)c1ccco1
Reactant: CN(C)N
Solvent: CCO
Product: CC(C)CCC(=NN(C)C)c1ccco1

Procedure:
A solution of 2-(4-methylvaleryl)furan (1 mmol) and N,N-dimethylhydrazine (1.5 mmol) in EtOH was heated at reflux for 24 h. Evaporation and distilation gave 2-(4-methylvaleryl)furan dimethylhydrazone as a brown oil.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)SC)([O-:3])=[O:2].N[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: NCCCCCO
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C(CCCCCO)CCCCCO

Procedure:
Heating 1-nitro-2,2-bis(methylthio)ethylene with an excess of 5-aminopentan-1-ol in ethanol gives 1,1-bis(5-hydroxypentyl)-2-nitroethylene, which may be treated with p-toluenesulphonyl chloride in pyridine and the product heated with thiourea in acetone to give 1,1-bis(5-(S-isothioureido)pentyl)-2-nitroethylene.