Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[N:8]=2)=[CH:3][CH:2]=1.[OH-].[NH4+:22]>CCOCC.O1CCCC1.O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([Cl:14])[N:10]=[C:11]([NH2:22])[N:12]=2)=[CH:5][CH:6]=1
Reactant: Clc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.9 %

Procedure:
A mixture of 2-[1,1′-biphenyl]-4-yl-4,6-dichloro-1,3,5-triazine (Example 63A) (0.804 g, 2.67 mmol) in 40 mL ether and concentrated ammonium hydroxide (2 mL, 30 mmol) in tetrahydrofuran (30 mL) was stirred at 0° C. for 60 minutes and at ambient temperature for 20 minutes. The reaction was reduced in volume, diluted with water, and the precipitate was collected, rinsed with water and ether, and dried to provide the desired compound (0.090 g, 12%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:35][CH:34](SC)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:43]1C=CC=C(C(OO)=O)C=1.[S:53]([O-:56])(O)=[O:54].[Na+]>ClCCl>[F:40][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:33][CH:34]([S:53]([CH3:43])(=[O:56])=[O:54])[CH2:35]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=S([O-])O
Reactant: CSC1CN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CC(S(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 0.25 g (0.42 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 10 ml dichloromethane were added 206 mg (70%, 0.84 mmol) 3-chloroperbenzoic acid at 0° C. After completed addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. An aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Basification with 1 N aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.16 g (60%) of the title compound as a white solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][NH:7][CH:8]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc(-c2ccccc2)c[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Temperature: 25 °C
Yield: 843.1 %

Procedure:
A solution of [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]carbamic acid tert-butyl ester (0.095 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH4 in THF (3.0 mL). The reaction was maintained at reflux for 2 h, cooled to room temperature, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated to afford 0.58 g (84%) of methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine as a light yellow oil (HPLC: 97% @ 254 nm and 214 nm). 1H NMR (300 MHz, CDCl3): δ 7.69 (2H, d, J=7.4 Hz), 7.36 (2H, t, J=7.6 Hz), 7.26 (1H, s), 7.25-7.20 (1H, m), 3.62 (1H, d, J=6.3 Hz), 2.35 (3H, s), 2.06 (1H, m), 0.99 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES+) (relative intensity): 230.2 (100) (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:29][N:17]1[C:18](=[O:28])[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=[C:16]1[O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: Cn1c(O[C@H]2CC[C@H](c3ccc(CO)cc3)CC2)nc(-c2ccncn2)cc1=O
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([C@H]3CC[C@H](Oc4nc(-c5ccncn5)cc(=O)n4C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[trans-4-(4-hydroxymethyl-phenyl)cyclohexyloxy]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (100 mg, 0.255 mmol) and triethylamine (51.6 mg, 0.510 mmol) in dichloromethane (1.3 ml) was added methanesulfonyl chloride (32.1 mg, 0.28 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into tetrahydrofuran (1.3 ml) and N,N-dimethylformamide (0.3 ml). 1-Methylpiperazine (30.6 mg, 0.306 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) was added to the solution. The mixture was stirred at 60° C. for 3 hours. The mixture was poured into water, and extracted with chloroform. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-{trans-4-[4-(4-methyl-piperazin-1-ylmethyl)phenyl]cyclohexyloxy}-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (51.1 mg, 0.108 mmol, 42%).
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O-:32])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(C)C(=O)O[C@@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)O[C@@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 90.0 mg (0.2854 mmol) of (−)-trans-4-({[(1R)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid 17 was reacted with 24.0 mg (0.2854 mmol) of sodium bicarbonate (NaHCO3) in 4 mL of a mixture of acetonitrile and water (1:1) to yield 96.3 mg (quant.) of the title compound 18 as a colorless powder. The enantiomeric excesses were determined with an analytical Waters 2690/ZQ LC/MS apparatus using a ChiralPak AD-RH column, an isocratic eluent consisting of 30% acetonitrile/70% water/0.05% formic acid, and a flowrate of 60 μL/min (Rf=15.0 min; e.e.=97.7%). 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=[N:10][C:9]=3[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=[N:10][C:9]=3[N:8]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: BrCC1CCCCC1
Reactant: CC(=O)CCn1cnc2[nH]c(=O)n(CC3CC3)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCn1cnc2c1c(=O)n(CC1CC1)c(=O)n2CC1CCCCC1

Procedure:
The title compound was prepared by stirring 1-cyclopropylmethyl-7-(3-oxobutyl)xanthine, 5 g, with 4.6 mls of bromomethylcyclohexane and 5.2 g of potassium carbonate in 30 ml DMF over 5 hours. After evaporation of the solvent the title compound was purified by column chromatography (ether).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH:8]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1)(=[O:4])=[O:3].[CH:36]1([C:42]23[CH2:49][CH2:48][N:45]([CH2:46][CH2:47]2)[CH2:44][CH2:43]3)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(#N)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:36]1([C:42]23[CH2:49][CH2:48][N+:45]([CH2:6][CH2:7][CH:8]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)[CH2:9][N:10]4[CH:14]=[CH:13][N:12]=[C:11]4[C:15](=[O:27])[C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=4)([CH2:44][CH2:43]2)[CH2:46][CH2:47]3)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CS(=O)(=O)OCCC(Cn1ccnc1C(=O)c1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)c(Cl)c1
Reactant: C1CCC(C23CCN(CC2)CC3)CC1
Solvent: CC#N
Product: CS(=O)(=O)[O-]
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)c1nccn1CC(CC[N+]12CCC(C3CCCCC3)(CC1)CC2)c1ccc(Cl)c(Cl)c1
Yield: 66.4 %

Procedure:
1-Methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-[2-(3-trifluoromethyl-4-fluorobenzoyl)imidazol-1-yl]butane (0.77 g) (see Preparation 80) and 4-cyclohexylquinuclidine (0.31 g) (see Preparation 1) were dissolved in acetonitrile (10 ml) and heated under reflux for 5 hours. The solvent was removed under reduced pressure, the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, dichloromethane:methanol to give 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(3-trifluoromethyl-4-fluorobenzoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate (0.69 g) as a white foam.
Reaction SMILES: [O-]CC.[Na+].[C:5](#[N:9])[CH2:6][C:7]#[N:8].[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:19]Cl>C(O)C>[NH2:8][C:7]1[C:6]([C:5]#[N:9])=[C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:18][N:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCl
Reactant: N#CCC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)nsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cold solution of sodium ethoxide (1.7 g, 25 mmol) in absolute ethanol (25 ml) was added malononitrile (1.65 g, 25 mmol), followed by addition of phenyl isothiocyanate (5.43 g, 25 mmol). The mixture was stirred at ambient temperature for 12 hours, cooled and then treated with freshly prepared aqueous chloramine solution (125 ml). After being stirred for 24 hours at ambient temperature, the mixture was filtered and the solid was dried in air. Crystallization from DMF-EtOH afforded colorless crystals (2.5 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH3:11].[Br:13]Br.[CH:15]([NH2:17])=[S:16]>C(Cl)Cl>[BrH:13].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:17]=[CH:15][S:16][C:10]=1[CH3:11]
Reactant: BrBr
Reactant: NC=S
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: Br
Product: Cc1scnc1-c1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To 2',4'-dichloropropiophenone (2.03 g; 0.01 mole) in methylene chloride (20 ml) was added excess bromine in methylene chloride (10 ml) dropwise at 20° C. The methylene chloride layer was washed with sodium sulphite solution and water, separated, dried (MgSO4) and evaporated. The residue was dissolved in ethanol (20 ml) and thioformamide (0.61 g; 0.01 mole) was added and the mixture stirred at 20° C. for 16 hours to give 4-(2',4'-dichlorophenyl)-5-methylthiazole hydrobromide (1.72 g; 53%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:30])=[CH:24]\[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 68.6 mg (0.53 mmol) of ethyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 91 mg (45% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4[F:61])=[C:51]([CH3:53])[N:52]=3)[C@H:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:41])C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])N(C)C)=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.ClN1C(=O)CCC1=O>>[F:61][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][CH2:83][OH:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[C@H:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:41])=[N:52][C:51]=1[CH3:53]
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(I)cc1F

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described in example 13) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 68-D and (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 68-F was omitted. HR-MS: calcd for C30H28FlN4O4 [M+H+] 655.1212. Found. 655.1210.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:14][OH:15].O.CCOCC>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)ccc1F
Reactant: NO
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
To a suspension of methyl 5-cyano-2-fluorobenzoate, obtained in step 2 (804.60 mg; 4.49 mmol; 1 eq.) in EtOH (8.05 mL) was added hydroxylamine (50% in water) (1.35 mL; 22.46 mmol; 5 eq.). The reaction mixture was stirred at RT for 1 h40. Water (25 mL) was added followed by Et2O (25 mL). Aqueous layer was extracted with Et2O (2×25 mL). The combined organic layers were then washed with NaCl sat. solution and dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow solid (931 mg; 98%). 1H NMR (DMSO-d6, 300 MHz) δ 9.78 (br s, 1H), 8.21 (dd, J=7.1, 2.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.38 (dd, J=10.8, 8.8 Hz, 1H), 5.97 (br s, 2H), 3.87 (s, 3H). HPLC (Method A), Rt 0.92 min (purity: 90.6%). LC/MS (Method B): 211.1 (M−H)−; 213.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C@H:25]1[CH2:24][CH2:23][C@H:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: NC1CCC(CN2CCCC2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (220 mg, 0.92 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)cyclohexanamine (200 mg, 1.1 mmol) to afford the desired product (67 mg, 19%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 10.88 (br s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 5.09-4.88 (m, 1H), 2.66 (br s, 7H), 2.46 (d, J=7.1 Hz, 2H), 2.37-2.25 (m, 2H), 2.08-1.76 (m, 6H), 1.72-1.55 (m, 1H), 1.51-1.12 (m, 4H); ESI MS m/z 387 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=O)[CH3:16])[C:8]1=[O:18])[CH3:2].[NH2:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[CH:32][N:31]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC(C)=O)C1=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 4-2 (540 mg, 1.4 mmol), 2-amino-3-formylpyridine (170 mg, 1.4 mmol; for prep. see JOC 1983,48, 3401) and proline (161 mg, 1.4 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil.
Reaction SMILES: ClCCC[N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.[CH:31](N(C(C)C)CC)([CH3:33])[CH3:32].[I-].[K+]>C(#N)C>[O:14]([C:11]1[CH:12]=[C:13]([CH2:32][CH2:31][CH2:33][N:28]2[CH2:29][CH2:30][CH:25]([C:18]3[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:16][N:17]=3)[CH2:26][CH2:27]2)[C:8]2[N:7]=[N:6][NH:5][C:9]=2[CH:10]=1)[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2nnn(CCCCl)c2c1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCCN2CCC(c3noc4ccccc34)CC2)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
N-(3-chloropropyl)-6-methoxyl benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-benzisoxazolyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 13.14 g N-(3-(6-methoxyl benzotriazolyl)propyl)-4-(3-benzisoxazolyl)piperidine (I-93) with a yield of 67.2%. ESI-MS [M+H]+: m/z 391.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:35])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[N:13][C:12]=2[NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH2:40])[CH2:37][CH2:38][NH2:39]>CN1C(=O)CCC1>[NH2:39][CH2:38][CH2:37][CH2:36][NH:40][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:35])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[N:13][C:12]=2[NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccc(Br)n2)c(NCCc2cccc(F)c2)n1
Reactant: NCCCN
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccc(NCCCN)n2)c(NCCc2cccc(F)c2)n1
Yield: 56.3 %

Procedure:
A solution of N-((6-bromopyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (50 mg, 0.095 mmol) and propane-1,3-diamine (396 ul, 4.75 mmol) in NMP was stirred in microwave at 15° C. for 15 min. The reaction mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O gave N-((6-(3-aminopropylamino)pyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (28 mg, 56%). LRMS (M+H+) m/z 524.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:19]#[N:20])=[CH:14][C:15]=3[CH2:16][CH2:17][CH:18]=2)O1.I[C:23]1[N:27]([CH2:28][C:29]([O-:31])=[O:30])[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O.O1CCO[CH2:41][CH2:40]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:40][CH3:41])=[O:30])[CH:26]=[N:25][CH:24]=1)=[CH:18][CH2:17][CH2:16]2)#[N:20]
Reactant: CC1(C)OB(C2=CCCc3cc(C#N)ccc32)OC1(C)C
Reactant: O=C([O-])Cn1cncc1I
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cn1cncc1C1=CCCc2cc(C#N)ccc21
Temperature: 80 °C

Procedure:
A mixture of 16.0 mmol of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7,8-dihydronaphthalene-2-carbonitrile, 18.0 mmol of (5-iodoimidazol-1-yl)acetate (Example 1f2), 0.74 mmol of tetrakis(triphenylphosphine)palladium(0) and 16 ml of 2M aqueous sodium carbonate solution in 100 ml of dioxane is heated at 80° C. for 5 hours. The reaction mixture is cooled, poured into water and extracted with tert-butyl methyl ether. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a colourless oil from the residue by flash chromatography (SiO2 60F). Rf=0.11 (dichloromethane-methanol 97:3); Rt=5.90 (gradient II).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (43 mg, 33%). MS (ISN) 509.0 [(M−H)−]; mp 273–274° C.