Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8]([C:11]1[C:12]([CH2:35]Br)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9].O>CN(C)C=O>[C:8]([C:11]1[C:12]([CH2:35][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9]
Reactant: c1nc[nH]n1
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C(C)=O)c(Cn3cncn3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
Oily sodium hydride (60%, 0.372 g) was added to a solution of 1H-1,2,4-triazole (0.594 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (3.3 g) was added, and the mixture was stirred at 80° C. for 40 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-acetyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline (1.4 g, 42%). This compound was recrystallized from ethanol to give colorless prisms, mp. 180°-181° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol (1.0 g, 4.5 mmol), phthalimide (1.0 g, 6.8 mmol) and triphenylphosphine (1.8 g, 6.8 mmol) in THF (20 mL), di-tert-butyl azodicarboxylate (1.6 g, 6.8 mmol) was added slowly at 0° C. The resulting mixture was stirred at 0° C. for 3 h. After concentrated concentrating under reduced pressure, the crude product was purified by silica gel column chromatography (eluting with 0-70% EtOAc in hexanes) to give a solid, which was further treated with DCM and hexanes to yield sub-title compound (1.55 g, 98%). LCMS calc. for C19H16N3O4 (M+H)+: m/z=350.1. Found: 350.3.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][C:37]=1[C:45]([F:46])([F:47])[F:48]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chloro-3-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.85-0.96 (m, 6H), 1.42-1.54 (m, 1H), 1.65 (ddd, J=13.82, 7.09, 6.97 Hz, 1H), 1.96 (dd, J=13.57, 7.21 Hz, 1H), 3.76 (t, J=7.70 Hz, 1H), 7.56-7.92 (m, 10H); Calcd for C26H21ClF6O2 (M+Na) 537.11, Found 537.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent 20 ml of dichlorometane and 20 ml of trifluoracetic acid was added and the mixture was stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then ethylacetate was added and the mixture was extracted two times with water. The aqueouos phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=9:1) to yield 2.1 g (65%) of (S)-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4] diazepin-2-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: Oc1cccc(CCCCCCCBr)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCCCc1cccc(OCc2ccccc2)c1

Procedure:
7-Bromo-1-(3-benzyloxy-phenyl)-heptane (10.2) was prepared as in 10.1 using 9.2 (0.4 g, 1.48 mmol), K2CO3 (0.612 g, 4.44 mmol) and benzyl bromide (0.278 g, 1.63 mmol). The title, compound (10.2) was isolated as a viscous liquid after purification by flash column chromatography (0.411 g, 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].F[B-](F)(F)F.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].CN(C=O)C>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:2]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-(2-bromo-4-(trifluoromethyl)phenyl)acetate (A57) (1.60 g, 5.38 mmol), PdCl2(PPh3)2 (189 mg, 269 μmmol), t-Bu3PH.BF4 (78.1 mg, 269 μmmol), CuI (51.3 mg, 269 μmol) and TMS-acetylene (1.52 mL, 10.8 mmol) in Et3N (10 mL) and anhydrous, degassed DMF (10 mL) was stirred at 80° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A58 as an orange liquid (1.56 g, 92%); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.87 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-A: rt 6.979 min; m/z 315 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([NH:15][CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=CNc1ccc2c(c1)[nH]c1cc(O)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)[nH]c2cc(NC=O)ccc23)cc1

Procedure:
Compound 2-(7-formamido-9H-carbazol-2-yloxy)ethyl 4-methylbenzenesulfonate (AD-CB-012P-WZ02039) was prepared using the same procedure for the preparation of AD-CB-012S-WZ01185) from N-(7-hydroxy-9H-carbazol-2-yl)formamide (100 mg) and ethane-1,2-diyl bis(4-methylbenzenesulfonate) (325 mg). (white solid, 22 mg, 12%). For the major rotomer: 1H NMR (400 MHz, acetone-d6) δ 10.19 (s, 1H), 9.31 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.90-7.81 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.69 (dd, J=8.4, 2.0 Hz, 1H), 4.43-4.41 (m, 2H), 4.29-4.27 (m, 2H); MS (ESI) m/z 425 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]1[N:10]=[C:11](O)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:8]([CH3:22])[C:9]1[N:10]=[C:11]([Cl:25])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(O)nc(N(C)Cc3ccccc3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(N(C)Cc3ccccc3)cc2c1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 3-(benzyl(methyl)amino)-6-methoxyisoquinolin-1-ol (1.8 g, 6.12 mmol) in POCl3 (10 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, and concentrated to give N-benzyl-1-chloro-6-methoxy-N-methylisoquinolin-3-amine (1.44 g, 4.60 mmol, 75% yield) as a yellow solid. MS: MS m/z 313.15(M++1).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[OH:30][CH:29]([C:28]1[CH:31]=[CH:32][C:25]([O:24][CH2:23][CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:27]=1)[CH2:13][C:12]#[N:14]
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(O)c1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To dry tetrahydrofuran (14 mL), n-butyl lithium (0.94 mL; a 1.6 M hexane solution) and dry acetonitrile (0.082 mL) were successively dropped at −78° C. After stirring for 30 minutes, a solution of 4-(3-phenylpropoxy)benzaldehyde (300 mg) in dry tetrahydrofuran (3 mL) was dropped into the mixture at −78° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixed solvent of diethyl ether and hexane and filtered to give the title compound (238 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][C:6]([O:9][CH2:10][CH:11]1[O:13][CH2:12]1)([CH3:8])[CH3:7].[OH-].[Na+]>B(F)(F)F.CCOCC.ClCCl>[C:6]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][O:3][CH2:2][CH2:1][OH:4])([CH3:5])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OCC1CO1
Reactant: OCCO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OCC(O)COCCO
Reaction time: 15 h
Yield: 71 %

Procedure:
To a solution of ethylene glycol (248 g, 4 moles) and boron trifluoride etherate catalyst (1 ml) in dichloromethane (20 ml) preheated to 45° C. was added t-BGE (130 g, 1 mole) dropwise at such a rate so as to maintain a gentle reflux. After completion of addition, stirring was continued for about 15 hours. The solution was then adjusted to pH 7.5 by addition of sodium hydroxide and the product removed by distillation. Tertiary butoxymethyl diethylene glycol was obtained in 71 percent yield having a boiling point of 105° C.-115° C./1 mm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1.ClCCl.[Br:19]Br>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[C:10]([Br:19])[C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1
Reactant: BrBr
Reactant: CCn1c(=O)ccc2c(C)nc(N)nc21
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2 mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL, 1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 h at room temperature. After that, the solvent was evaporated nearly 80% volume of reaction mixture under vacuum, and then acetone was added to give 3.54 g 2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid. LC/MS: Calculated for C10H11BrN4O (283.12). Found: 285.15 (M+2). HPLC analytical purity: 97.7%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:41][N:42]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C[Si](C)(C)ON>CN(C=O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21](=[O:23])[NH:42][OH:41])=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C1CCC(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)ON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H]1CC[C@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid (prepared as described in example 92; 0.2 g, 0.36 mmol) was dissolved in DMF (5 mL.) and 1-hydroxybenzotriazole (53 mg, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and N,N-diisopropylethylamine (85 μL, 0.50 mmol) and O-(trimethylsilyl)hydroxylamine (60 μL, 0.50 mmol) were added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and was washed with a saturated aqueous solution of sodium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and glacial acetic acid (9:1) This afforded 95 mg (46%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:14][CH2:13][N:15]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.15 g (16.7 mmol) of 2-chloro-6-hydroxy-benzothiazole are dissolved in 50 ml of dimethylformamide and after the addition of 5.68 g (33 mmol) of 2-diethylamino-ethyl chloride-hydrochloride and 8.3 g (60 mmol) of potassium carbonate the mixture was stirred for 20 hours at ambient temperature. It was then added to water and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is purified by column chromatography on neutral aluminium oxide (eluant: petroleum ether/ethyl acetate=6:1). Yield: 3.9 g (81.7% of theory), oil, 1H-NMR spectrum (200 MHz, CDCl3, signals at ppm): 1.08 (t, 6H); 2.65 (q, 4H); 2.9 (t, 2H); 4.09 (t, 2H); 7.08 (dd, 1H); 7.24 (d, 1H); 7.8 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:15])[Cl:14])[N:3]=1.[C:16](O)(=[O:18])C.C(OC=O)=O>C(#N)C>[CH:16]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:14])[Cl:15])[N:3]=1)=[O:18]
Reactant: Nc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: CC#N
Product: O=CNc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of 2.7 g (0.01 mol) of 2-amino-4-chloro-6-{[(2,2-dichloro-cyclopropyl)methyl]amino}pyrimidine in 300 ml of acetonitrile was added dropwise, while stirring, at room temperature over a period of 15 minutes to a solution of 0.9 gm (0.012 mol) of acetic acid-formic acid anhydride in 5 ml of acetonitrile. After stirring the mixture for about 30 hours at room temperature the solvent was distilled off in vacuo, and the residue was treated twice by dissolving it in about 30 ml of toluene and then distilling the toluene off again. The raw product was purified by column chromatography (150 gm silica gel; eluant: Diisopropyl ether/ethyl acetate 9:1), yielding the title compound as white crystals.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH:1]1([C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)C1CCCCC1
Yield: 65 %

Procedure:
The title compound (1.1 g, 65%) as a colorless oil was prepared from cyclohexyl-magnesium bromide and methyl chlorooxoacetate by the procedures described in F. Babudri et al., Tetrahedron, 52 (42), pp. 13512-20 (1996).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=[N:14]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCCC#Cc1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C(#Cc1ccccn1)CCCCn1nc2ccccc2n1
Yield: 13.3 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol) and benzotriazole (125 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole (38 mg, 0.14 mmol, 13%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole (48 mg, 0.17 mmol, 16%) as a brown oil.
Reaction SMILES: B.CSC.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)Cc1cc(F)cc(CBr)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1cc(F)cc(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Borane-methyl sulfide complex (2M in THF, 17.4 mL) was added dropwise over 10 minutes to a solution of 2-(3-(bromomethyl)-5-fluorophenyl)acetic acid (example 41, step a) (4.3 g) in THF (60 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at 20° C. for 1 hour. The reaction mixture was quenched by dropwise addition of methanol and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 3.7 g.
Reaction SMILES: Cl[C:2]1C=CC(C#N)=CN=1.[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:23]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[Cl:39])[N:22]=2)[CH:14]=[CH:13][C:12]=1[N+]([O-])=O>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:23]1[N:22]=[C:21]([NH:20][CH2:19][CH2:18][NH:17][C:15]2[N:16]=[CH:2][C:12]([C:11]#[N:10])=[CH:13][CH:14]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[NH:31][CH:30]=[CH:29][N:28]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazolyl-2-pyridyl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 2-chloropyridine-5-carbonitrile using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[N:14]1.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][O:19][CH3:22])[CH:15]=[N:14]1
Reactant: OCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol (1.5 g), sodium hydride (0.15 g) and methyl iodide (0.7 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours and left over the weekend. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methoxymethyl-2H-1,2,3-triazole, m.p. 32°-33°. (Compound 20)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 43.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (120 mg) as colorless prisms, mp 217°-219° C.